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Keywords:

  • kinesin;
  • mitosis;
  • tumorigenesis;
  • biomarker;
  • molecular-targeted therapy

Abstract

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010. © 2010 American Cancer Society.

The kinesin was discovered first in 1985.1 To date, a total of 45 murine and human kinesin superfamily proteins (KIFs) have been identified and classified into 14 families (termed kinesin-1 to kinesin-14) according to standardized nomenclature for kinesins.2, 3 KIFs are a conserved class of microtubule-dependent molecular motor proteins that have adenosine triphosphatase (ATPase) activity and motion characteristics.4 The active movement of kinesins supports several cellular functions, such as mitosis, meiosis, and the transport of macromolecules (eg, axonal transport).5 In mitosis of eukaryotic cells, kinesins participate in spindle formation, chromosome congression and alignment, and cytokinesis.6 There is indication that the abnormal expression and function of kinesins plays a key role in the development or progression of many kinds of human cancers. Better understanding of kinesin protein functions may translate into the development of molecular-targeted therapy for various human cancers.7 In addition, the evaluation of kinesin expression may identify biomarkers for the early detection of human cancer and a better indication of prognosis for cancer patients.

Through analogic analysis of the protein structures of Kinesin-1, it is believed that kinesins form a heterodimer with 4 functional domains referred to as the 1) motor, 2) neck, 3) stalk, and 4) tail. The motor domain is connected through a short, flexible neck-linker domain to the stalk domain. The stalk domain is a long, central coil that ends in the tail domain. The “head” or motor domain consists of up to 360 amino acids with an ATP-binding site and an adjacent microtubule-binding site. The function of the motor domain is to hydrolyze ATP to generate the energy needed for movement of the proteins along microtubule fibers. The neck domain is often subtype-specific. In different kinesins, this subtype-specific neck domain is essential for motility direction of the protein. The stalk domain is important for the interaction with other subunits of the holoenzyme and intertwines to form the kinesin dimer. The tail domain is localized at the opposite end of the protein and functions to interact with the transportation of cargo molecules, including proteins, lipids, or nucleic acids.8-10 The 14 families of kinesins can be grouped into N-kinesins, M-kinesins, and C-kinesins, which contain their motor domain at the amino terminus, in the middle, or at the carboxyl terminus, respectively. N-kinesins drive microtubule plus end-directed transport, C-kinesins drive minus end-directed transport, and M-kinesins depolymerize microtubules.11 Among the KIFs, the motor domain is highly conserved, whereas the “stalk/tail” region is highly divergent (Fig. 1). This reflects the diverse cellular functions of kinesins, which range from synaptic vesicle transportation, to the axon of neurons, to chromosomal transportation during mitosis.4

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Figure 1. The structure and functional domains of kinesin family proteins (KIFs) are illustrated. In general, kinesins comprise a kinesin motor domain and a coiled-coil domain. There also are specific domains or regions, such as the pleckstrin homology (PH) domain of KIF1B, the DNA binding domain of kinesin-like DNA binding protein (Kid), and nuclear localization signals (NLSs) of KIF4A, mitotic kinesin-like protein 1 (MKLP1), Kid, and mitotic centromere-associated kinesin (MCAK). KHC indicates kinesin heavy chain; Eg5, a kinesin spindle protein (KSP); CENP-E, centrosome-associated protein E; ATP, adenosine triphosphate.

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In general, kinesins act as molecular motors to transport cargo along microtubules in eukaryotic cells. In addition, kinesins provide power for a variety of transportation needs during cell cycle progression, including mitosis and meiosis. Kinesins also serve roles in ciliary and flagellar genesis, microtubule polymer dynamics, and signal transduction.12 However, different subtypes of the kinesin protein family may participate in different functions in cells. For example, kinesin-1, kinesin-12, kinesin-3, kinesin-4, kinesin-12, and kinesin-14 reportedly transport organelles; whereas kinisen-1, kinesin-4, kinesin-5, kinesin-6, kinesin-7, kinesin-8, kinesin-10, kinesin-12, and kinesin-13 mainly participate in cell mitosis, particularly in spindle formation, chromosomal and nuclear movement, and cytokinesis. It has been demonstrated that kinesin-11 participates in signal transduction. However, the precise function of kinesin-9 remains unclear.4

To date, many studies have demonstrated that altered expression of kinesins is associated with the development and progression of various human cancers.13-23 Abnormal kinesin expression alters the equal distribution of genetic materials during cell mitosis because of chromosome hypercondensation, aberrant spindle formation, anaphase bridges, defective cytokinesis, aneuploidy, and mitotic arrest. The loss or gain of genetic material will lead to numerous defects in the daughter cells and may result in carcinogenesis with an aggressive behavior of corresponding tumor cells. Therefore, the detection of abnormal kinesin protein or messenger RNA (mRNA) expression could be used as a biomarker for early tumor diagnosis or to predict the survival of patients with cancer. Moreover, because human cancer is a gene-related disease with abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancers. Indeed, several such drugs are being studied successfully in clinical trials. In this review, we discuss in detail the role of KIFs in tumorigenesis and progression as well as their clinical value as biomarkers and molecular targets for cancer therapy. Important aspects of KIFs in relation to cancer manifestation, progression, and therapy are summarized in Table 1.

Table 1. Kinesin Protein Families and Their Association With Tumorigenesis and Progression
Standardized NameMember(s)Gene MappingReported Function (References)Relation With Tumor (References)Clinical Value (References)
  1. HsuKHC/KIF5B indicates human motor protein kinesin-1 heavy chain/kinesin family protein 5B; KIF, kinesin family protein; Eg5, a kinesin spindle protein; mRNA, messenger RNA; MKLP1, mitotic kinesin-like protein 1; CENP-E, centrosome-associated protein E; MACK, mitotic centromere-associated kinesin.

Kinesin-1HsuKHC/KIF5B10p11.22Lysosome membrane and mitochondria transportation (Nakata & Hirokawa 1995,24 Tanaka 199825)Up-regulated in several types of cancer tissues (Cardoso 2009,22 Dyrskjot 2004,27 Hippo 2002,28 Nindl 2006,29 Richardson 200630)A promising target for cancer therapy
Kinesin-2KIF3A5q31.1Organelle, intraflagellar transportation and spermatogenesis (Miki 20054)Tumorigenesis and metastasis of breast cancer, renal cell carcinoma (Lukong & Richard 2008,13 Jimbo 200238) 
 KIF3B20q11.21   
Kinesin-3KIF1B1p36.2Mitochondria and synaptic vesicle transportation (Nangaku 1994,40 Matsushita 200441)Metastasis of nervous system tumors and breast cancer (Li 2009,14 Bagchi 200742)mRNA is a marker for predicting prognosis in breast cancer (Li 200914)
 KIF141q32.1Cytokinesis (Carleton 2006,45 Gruneberg 200646)Tumorigenesis of primary breast, lung and retinoblastoma tumors (Corson 2006,15 Corson 200547)A prognostic indicator of outcome in breast and lung cancer (Corson 2006,15 Feng 2006,16 Corson 200717)
Kinesin-4KIF4AXq13.1Mitosis, including chromosome condensation (Zhu 2005,6 Mazumdar 200448)Tumorigenesis of cervical cancer and nonsmall cell lung cancer (Taniwaki 2007,18 Narayan 200749)A promising target for cancer therapy
 KIF715q26.1A major inhibitor of the mammalian Hedghog pathway (Cheung 200951)Tumorigenesis and metastasis of many tumors (Feng 2005,52 Tremblay 2009,53 Sarangi 200954) 
Kinesin-5Eg5/KIF1110q24.1Essential for cell proliferation; plays an important role in mitosis (Castillo 2007,20 Le Guellec 199155)High expression in many tumors and related to tumorigenesis (Castillo 2007,20 Le Guellec 199155)A potent target for cancer therapy
Kinesin-6MKLP1/KIF2315q23Cytokinesis (Chen 200559)Deletion can inhibit cytokinesis of tumor cells (Chen 200559)Potential target for cancer therapy
 MKLP2/KIF20A5q31.2Spindle assembly of mitosis (Cesario 200660)Overexpressed in pancreatic ductal adenocarcinoma cells (Taniuchi 200564)Potential target for cancer therapy
Kinesin-7CENP-E/KIF104q24-q25Aligns chromosomes and modulates the spindle checkpoint (Wood 1997,65 Kapoor 2006,66 Schaar 1997,67 Yao 2000,68 Mao 200369)Inhibition of CENP-E can inhibit growth in many tumor types (Weaver 2003,70 McEwen 2001,71 Chua 2007,72 Sutton 2007,73, 74 Schafer-Hales 2007,75 Ashar 200076)Inhibitions of CENP-E currently are undergoing clinical trials
Kinesin-8KIF18A11p14.1Chromosome congression and alignment (Stumpff 200879)The homologous gene SW108 is expressed at the mRNA level in the majority of tumor cells (Shichijo 200523)A potential target for cancer therapy
Kinesin-10Kid/KIF2216p11.2Chromosome arm orientation, chromosome oscillation and congression (Levesque & Compton 2001,82 Yajima 200383)Overexpressed in proliferating breast cancer but down-regulated in invasive and metastatic tissue (Feng 200616)mRNA expression has been shown to be a biomarker of diagnosis and prognostic indicator of outcome in breast cancer
Kinesin-13MCAK/KIF2C1p34.1Kinetochore-microtubule attachment (Ishikawa 200889)Tumorigenesis and metastasis of many tumors(Nakamura 2007,88 Ishikawa 2008,89 Shimo 2008,90 Scanlan 200291)A potential target for cancer therapy and for predicting lymph node metastasis
Kinesin-14KIFC16p21.3Spindle assembly (Cai 200992)Essential for extra centrosome-containing cancer cells (Kwon 200893)A potential target for cancer therapy

Kinesin-1 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Kinesin-1 was referred to previously as conventional kinesin: kinesin heavy chain (KHC). These proteins are capable of using chemical energy from ATP hydrolysis to generate mechanical force. In the presence of ATP, kinesin-1 binds to and moves microtubules. The ability to translocate along the microtubule lattice has led to the classification of kinesin-1 as a microtubule motor protein. However, the mechanism by which molecular motor proteins convert energy from ATP hydrolysis into mechanical force remains unclear. Kinesin-1 is abundant in virtually all cell types at all stages of development and appears to be free in the cytoplasm. However, some kinesin-1 is associated with various membrane-bound organelles, including small vesicles and endoplasmic reticulum and membranes that lie between the endoplasmic reticulum and Golgi body. One of its members, KIF5B, participates mainly in lysosome membrane and mitochondria transportation.24, 25 Hakimi et al26 demonstrated that KIF5B functions as a catalytic subunit of both nuclear factor 1 (NF-1) (neurofibromin) and NF-2 (merlin) complex. Mutations in either of these NF genes result in the development of neurofibromatosis, a condition that predisposes individuals to develop a variety of benign and malignant tumors of the central and peripheral nervous systems. This indicates that KIF5B may be associated with neurofibromatosis. Furthermore, it is reported that KIF5B mRNA was up-regulated in several types of cancer tissues, including cancers of the bladder, stomach, skin, and breast.27-30 In addition, Cardoso et al22 observed that KIF5B protein was highly expressed in various cancer cells, and the depletion of KIF5B in HeLa cells induced lysosomal leakage and cell death. The results from those studies suggest that inhibition of KIF5B expression may be a promising target in the control of these cancers.

Kinesin-2 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

It is believed that kinesin-2 drives membrane-associated movements in axons, axonemes, and melanophores and contains several proteins, such as KIF3A and KIF3B. These proteins form a complex with other proteins to exert their biologic function in the cells. For example, Mans et al31 reported that ATP-dependent motor complex kinesin-2 endogenously bound the full-length variant of von Hippel-Lindau tumor suppressor protein (pVHL30) in primary kidney cells and increased its stability with microtubules. The pVHL participates in many cellular processes, including oxygen sensing, microtubule stability, and primary cilia regulation. Inactivation of the VHL gene by mutations/deletions caused sporadic renal cell carcinoma and central nervous system hemangioblastoma.32 Furthermore, Staller et al33 demonstrated that pVHL inhibited tumor metastasis through inactivation of hypoxia-induced factor and inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) gene expression.

Kinesin-associated protein 3 (KAP3) forms a heterotrimer with KIF3A/3B through its binding to the tail domain of the KIF3A/3B heterodimer34 and links KIF3A/3B with various cargo proteins, such as adenomatous polyposis coli (APC)35 and breast tumor kinase (BRK).13 Mutations in the APC gene affect the cell cycle and promote tumor cell growth but suppress differentiation and apoptosis, possibly because the mutant APC protein derived from cancer cells is unable to accumulate efficiently in clusters that are necessary for the interaction of APC with KAP3-KIF3A-KIF3B to form a functional complex.36-38 In addition, conditional inactivation of the KAP3 subunit of the KIF3 complex in neural progenitor cells resulted in embryonic brain tumors.39 Lukong and Richard13 demonstrated that KAP3 knockdown resulted in the suppression of BRK-induced migration of breast cancer cells and that the C-terminal deletion mutant of KAP3 acted as a dominant negative in BRK-induced cell migration. However, another study by Jimbo et al38 indicated that KAP3-ΔArm5-transfected Madin-Darby canine kidney cells increased cell migration. These conflicting data indicate that functions of the KAP3-KIF3A-KIF3B complex may depend on cell type. Further investigations will be necessary to elucidate the role of KAP3-KIF3A-KIF3B in cells.

Kinesin-3 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Kinesin-3 family proteins function as organelle transporters. KIF1B, a kinesin-3 member, participates mainly in the transportation of mitochondria and synaptic vesicles.40, 41KIF1B expression is lost in many different tumor cells, indicating that KIF1B insufficiency may lead to tumorigenesis in normal cells, especially when combined with the loss of other contiguous 1p genes like the chromodomain helicase DNA binding protein 5 (CHD5) gene.42, 43 Schlisio et al19 demonstrated that KIF1Bβ is necessary for inducing neuronal apoptosis and that decreased KIF1Bβ levels can protect the neural cells against apoptosis and, in turn, cause neuroblastoma and pheochromocytoma. However, complete loss of KIF1Bβ promotes neuronal apoptosis.44 These conflicting data indicate that the KIF1B gene plays different roles in tumorigenesis and progression. Indeed, our previous study indicated that the 5-year disease-free survival and metastasis-free survival rates among patients with breast cancer who had low levels of KIF1B mRNA were poorer than the rates among patients who had high levels of KIF1B mRNA.14 We demonstrated that the detection of KIF1B mRNA is an independent molecular marker for predicting the prognosis of patients with breast cancer.

Furthermore, recent small interfering RNA (siRNA)-based gene knockdown studies have verified the role of KIF14, another kinesin-3 member, in the cytokinesis of eukaryotic cells.45, 46 KIF14 is a microtubule motor that is amplified and overexpressed in breast cancer, lung cancer, and retinoblastoma.15, 47 It has been demonstrated that altered KIF14 mRNA expression is a prognostic indicator for patients with breast cancer and lung cancer.15, 17 The absence of KIF14 in HeLa cells reportedly resulted in a failure to complete cytokinesis, producing binucleated cells that underwent apoptosis after failed mitosis.45 Functionally, KIF14 protein is localized at the spindle midzone (the area formed between retreating chromosomes as they segregate toward the spindle poles in anaphase) and the midbody (the cytoplasmic bridge that connects 2 daughter cells at the end of cytokinesis in telophase).45, 46 Therefore, targeting KIF14 may be a novel strategy for cancer therapy.

Kinesin-4 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Among kinesin proteins, KIF4A plays important roles in the regulation of eukaryotic cell mitosis by participating in chromosome condensation and segregation, spindle segregation, and cytokinesis during cell mitosis.6, 48 Alteration of KIF4A expression has been observed in different human cancers. For example, Narayan et al49 reported that the expression of KIF4A mRNA in cervical cancer was much higher than that in normal tissues. Taniwaki et al18 demonstrated that the KIF4A gene was activated in nonsmall cell lung cancer (NSCLC) cells and that treatment of NSCLC cells with specific siRNA to knockdown KIF4A expression resulted in the suppression of cancer cell growth. Moreover, patients with NSCLC who had KIF4A-positive tumors had a shorter cancer-free survival than patients who had KIF4A-negative tumors. In addition, KIF4A was classified as 1 of the typical cancer testis antigens. The selective inhibition of KIF4A activity by molecular-targeted agents was a promising therapeutic strategy that was expected to have powerful biologic antitumor activity with minimal adverse events. However, some conflicting results have been reported recently. For example, Mazumdar et al50 performed in vivo and in vitro experiments to demonstrate that loss of KIF4A leads to multiple mitotic defects, including chromosome misalignments, spindle defects, and aberrant cytokinesis, which may cause tumorigenesis. Further studies will be required to gain a better understanding of the role of KIF4A in cancer development and progression.

In addition, KIF7, another member of the family, is a potent inhibitor of the mammalian Hedgehog (Hh) pathway.51 The latter is activated in many kinds of tumor cells, and recent evidence suggests that blocking aberrant Hh pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancers.52-54 These data suggest that the induction of KIF7 expression or activity may control human cancers effectively and, thus, may be used as a therapeutic tool.

Kinesin-5 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Kinesin spindle proteins (KSPs), such as KIF11/Eg5, belong to the kinesin-5 family and play an important role in cell mitosis through bipolar spindle assembly and segregation. Thus, KSPs are essential for cell growth and survival. In nonproliferating cells and tissues in adults, the expression of KSP remains undetectable, whereas its expression is prominent in proliferating cells and tissues during development.20, 55 Increased expression of Eg5 reportedly is associated with tumorigenesis. For example, Castillo et al20 demonstrated that transgenic mice that overexpressed Eg5 were prone to the development of a variety of tumors. Dimethylenastron, an Eg5 inhibitor, effectively inhibited tumor cell proliferation and induced apoptosis of pancreatic cancer cells and in nude mouse xenografts.56 To date, several inhibitors of Eg5 (eg, monastrol and ispinesib) have been used successfully in the clinic. Liu et al57 observed that the suppression of Eg5 by monastrol arrested mitosis and induced apoptosis but up-regulated heat-shock protein 70 (Hsp70) in human multiple myeloma cells. The up-regulation of Hsp70 enhanced antiapoptosis in cells as an unexpected side effect. This finding indicates that a combination of Eg5 inhibitors with agents that abrogate Hsp70 induction may be useful as therapy for myeloma. Saijo et al58 reported that the response rate of patients with Eg5-positive NSCLC to chemotherapy was 37% compared with 10% in patients with Eg5-negative NSCLC, suggesting that the detection of Eg5 expression may be a useful biomarker for predicting the response to antimitotic agents plus platinum chemotherapy in patients with advanced NSCLC.

Kinesin-6 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

A kinesin-6 member, mitotic kinesin-like protein 1 (MKLP1) (also known as KIF23) is essential for cytokinesis. Chen et al59 observed that reduced MKLP1 expression led to severe inhibition of proper midbody formation and completion of cytokinesis during cell mitosis, thus, resulting in the death (apoptosis) of tumor cells by using RNA interference (RNAi) to knockdown MKLP1 expression. This finding indicates that targeting MKLP1 may be used to develop cancer therapy drugs.

Furthermore, MKLP2/KIF20A, another member of kinesin-6 family, also participates in spindle assembly during mitosis.60 By using microarray analysis, Wonsey and Follettie61 observed that forkhead box M1 (FoxM1) up-regulated MKLP2, which was essential for faithful mitosis, and the expression of FoxM1 was correlated with the proliferative status of a variety of normal and transformed cell types. Consistent with a role in proliferation, elevated expression of FOXM1 has been reported in both basal cell carcinoma of the skin and in hepatocellular carcinoma.62, 63 In addition, Taniuchi et al64 reported that pancreatic ductal adenocarcinoma strongly overexpressed MKLP2 protein, and knockdown of endogenous MKLP2 levels in pancreatic adenocarcinoma cell lines using siRNA dramatically attenuated tumor cell growth. These findings indicate that MKLP2 also may be a target for cancer therapy.

Kinesin-7 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Centrosome-associated protein-E (CENP-E) (also known as KIF10) is localized at kinetochores that have 2 functions. Acting as a motor protein, CENP-E positions chromosomes on the metaphase plate by sliding unattached kinetochores toward the spindle equator along microtubule bundles referred to as kinetochore fibers (K-fibers).65-67 In addition, CENP-E modulates the spindle checkpoint by directly binding to the mitotic checkpoint Bub1-related protein BubR1 and stimulating its kinase activity, representing a link between the attachment of spindle microtubules and the mitotic checkpoint-signaling cascade.68, 69 Loss of CENP-E expression or altered function of CENP-E leads to inhibition of chromosome alignment during mitosis, resulting in the initiation of checkpoint activation and a delay in the completion of cell mitosis.70, 71 The inhibition of CENP-E using a potent and selective CENP-E inhibitor GSK923295A reportedly delayed the duration of cell mitosis, as characterized by the presence of lagging, nonequatorially aligned chromosomes associated with the spindle pole, and this was followed by apoptosis.72, 73 Several investigators have reported the efficacy of GSK923295A in nude mouse xenografts,74 and its antitumor effects are the subject of current phase 1 clinical trials in patients with advanced solid tumors. In addition, CENP-E is regulated functionally by farnesylation; thus, the suppression of CENP-E farnesylation using a farnesyl transferase inhibitor, lonafarnib, also may have antitumor effects. Indeed, such an inhibitor is being evaluated currently in multiple clinical trials for the treatment of solid tumors.75, 76 However, once CENP-E expression is altered in cells, the chromosomes cannot separate normally, and this may result in aneuploidy, which is a hallmark in most solid cancers, such as hepatocellular carcinoma (HCC).77 Liu et al78 observed that CENP-E expression was reduced in HCC tissue, and low CENP-E expression resulted in aneuploidy in the normal liver cell line LO2. However, those authors did not provide direct evidence that reduced expression of CENP-E can initiate hepatocarcinogenesis. Further studies are needed to gain a better understanding of the role of CENP-E in tumorigenesis.

Kinesin-8 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

It has been demonstrated that kinesin-8 family member KIF18A plays key roles in the regulation of chromosome congression during prometaphase and in the maintenance of chromosome alignment during metaphase.79 The use of RNAi to knockdown KIF18A expression resulted in aberrantly elongated spindle microtubules, loss of tension across sister kinetochores, activation of the spindle checkpoint, and mitotic arrest.4, 80 Shichijo et al23 studied a tumor-associated antigen recognized by cytotoxic T lymphocytes that has high homology with KIF18A. They observed that this unique gene was expressed at high levels in the majority of cancer cells but not in many normal tissues, with the exception of testis and lung. In addition, Zusev and Benayahu81 reported that both estrogen and estrogen receptor (ER)-α could up-regulate the expression of KIF18A mRNA and protein in vivo and in vitro. This finding indicates that KIF18A may be associated with ER-related cancers. Together, these results indicate that KIF18A may be a potential target for cancer therapy.

Kinesin-10 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

The kinesin-like DNA binding protein (Kid)/kinesin-like 4 (KNSL4)/KIF22 belongs to the kinesin-10 family, and studies have demonstrated that it is involved in chromosome arm orientation, chromosome oscillation, and congression on the metaphase plate of the mitotic spindle.82, 83 Kid, as a DNA binding protein, functions as a transcription factor (trans-acting factor) by binding to the corresponding regulatory DNA sequence (cis-acting element) of the target genes.84 In addition to the DNA-binding domain, Kid also contains 2 conventional basic nuclear localization signals (NLSs).85 Therefore, it localizes to the nucleus in normal cells. However, Bruzzoni-Giovanelli et al86 reported that Kid expression was more diffuse (cytoplasmic) in tumor cells. Their report indicated that NSLs may mutate in tumor cells. In our previous study, we observed that KNSL4 mRNA and its coded protein, Kid, were not detectable in normal tissues but were overexpressed in proliferating breast cancer tissues, whereas they were down-regulated in invasive and metastatic breast cancer cells. In addition, patients who had breast cancer with low KNSL4 mRNA expression had much a poorer disease-free survival rate than patients with higher expression (unpublished data). Therefore, the detection of KNSL4 mRNA expression may be evaluated further as a biomarker in breast cancer.

Kinesin-13 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

The kinesin-13 family, namely, the mitotic centromere-associated kinesin (MCAK)/kinesin-like 6 (KNSL6)/KIF2C protein, is essential for kinetochore-microtubule attachment during spindle formation in cell mitosis and possesses microtubule depolymerizing activity.87 A study of its association with human cancer revealed that MCAK was highly expressed in colorectal and gastric cancer tissues compared with its expression in corresponding normal tissues. This elevated expression was associated with lymph node metastasis, venous invasion, and peritoneal dissemination of colorectal cancer cells.88, 89 Again, The expression of MCAK mRNA in patients with colorectal cancer was related to a much poorer survival rate than that in patients who had low levels of MCAK mRNA expression.89 Furthermore, the suppression of MCAK expression in breast cancer cells inhibited tumor growth.90 These findings suggest that targeting the MCAK gene may effectively control human cancers and that the detection of MCAK expression could be used as a tumor biomarker for early diagnosis or prognosis. Indeed, a recent study demonstrated that MCAK protein was detected in the peripheral blood stream of patients with colon cancer,91 and this finding should be evaluated further to determine whether the detection of MCAK in blood can be used for early diagnosis or for predicting tumor metastasis.

Kinesin-14 Family

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

The Kinesin-14 proteins (formerly known as the C-terminal motor proteins) have in common a C-terminal motor domain, differing from other kinesin proteins. It has been observed that at least 4 members of the group (Drosophila melanogaster nonclaret disjunctional protein [DmNcd], Saccharomyces cervisae kinesin-like protein [ScKAR3], Cricetulus griseus Chinese hamster ovary protein 2 [CgCHO2], and Arabidopsis thaliana kinesin-like calmodulin binding protein [AtKCBP]) are minus end-directed motors, in contrast to the plus end-directed motility of other kinesin proteins. These minus end-directed motors of kinesin-14 family proteins that cross-link microtubules play key roles during spindle assembly. KIFC1, a normally nonessential kinesin motor, promotes the outward movement of the spindle poles and increases the half-spindle length of the monopolar spindle. It is essential for the viability of certain extra centrosome-containing cancer cells.92, 93 Knockdown of human KIFC1 gene expression with siRNA induced a dramatic increase in multipolar anaphases, in which nearly 100% of cells contained extra centrosomes, but had no effect on cell division and viability in control cells, raising the prospects of a tumor-selective kinesin drug target.93 In addition, resistance to chemotherapy remains a major barrier to the successful treatment of cancer. De et al94 demonstrated that breast cancer cells with overexpressed KIFC1 became more resistant to docetaxel. This finding may lead to novel therapeutic approaches in which KIFC1 inhibitors are paired with taxanes.

Summary and Future Directions

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

It has not been long since the first kinesin was discovered, and 14 kinesin family members, each containing various proteins, have been identified. These microtubule-based molecular motors play an essential role in eukaryotic cell mitosis and macromolecule transportation. Alteration of their expression and functions leads to human disease, including cancer development and progression. For example, alterations of KIF3,13 KIF1B,14 KIF14,15 and Kid16 proteins were observed in breast cancer; KIF1417 and KIF4A18 were altered in lung cancer; and KIF1B was down-regulated in neurofibroma.19 In addition, altered expression of EG5,20 CENP-E,21 KIF5B,22 and KIF18A23 proteins was associated with the development of different human cancers. Thus, an analysis of their expression may serve as useful tools for the early detection of tumorigenesis and for better predictions of prognosis for patients with cancer. Targeting these proteins in human cancer cells will be a novel antitumor strategy in the effective control of human cancers.

Although the functions of kinesin proteins include mitosis and transportation of macromolecules in the cells, and alteration of their expression leads to carcinogenesis and cancer progression, the underlying molecular mechanisms responsible for tumor development and progression remain to be elucidated. Summarizing from previous studies, the expression of KIFs is regulated by the upstream transcription factor. For example, KIF1Bβ is regulated by egl9 homolog 3 (EglN3),19MKLP1 is regulated by cut-like homeobox 1 (CUX1) and E2F transcription factor 1 (E2F1),95MKLP2 is regulated by forkhead box M1 (FoxM1),61 and MCAK is regulated by Sp transcription factor 1 (Sp1) and E2F1.96 The phosphorylation of KIFs reduced their binding to microtubules97, 98 and changed the localization and microtubule depolymerizing activity of KIF.99 After executing their functions (such as regulation of the cell cycle), KIFs are degraded through the ubiquitin proteasome pathway at the anaphase of cell cycles (such as Kid100 and KIF18A101). However, this is not true for Eg5, which is repressed transcriptionally by Parkin, an E3 ubiquitin ligase, through blocking c-Jun binding to the AP1 site of the Eg5 gene promoter.102 Taking these findings together, in future studies, the molecular mechanisms responsible for the dysfunctions and alterations of these transporters warrant further investigation. For example, the cause of aberrant KIF expression and the translocation of KIFs in cells for altered gene signaling need to be investigated. Meanwhile, it is urgently important to determine the causes of abnormal mitosis in cells, which may lead to a better understanding of fundamental cell biology. Further studies also will clarify how these genes participate to change cell behaviors, such as migration and proliferation, and whether these genes have the ability to compensate each other's functions in the cells. Answers to these questions will provide crucial clues for clarifying the cellular functions and roles of kinesin proteins, helping us to develop novel strategies for better early detection and treatment of different human cancers.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES

Supported by grants from The National Natural Science Foundation of China (no. 30471671 and no. 30872518), the Applied Basic Research Program of Tianjin (no. 06YFJMJC12900), the Major Program of Applied Basic Research Projects of Tianjin (no. 09JCZDJC19800), and the Program for Changjiang Scholars and Innovative Research Team in University by the Ministry of Education (no. URT0743).

REFERENCES

  1. Top of page
  2. Abstract
  3. Kinesin-1 Family
  4. Kinesin-2 Family
  5. Kinesin-3 Family
  6. Kinesin-4 Family
  7. Kinesin-5 Family
  8. Kinesin-6 Family
  9. Kinesin-7 Family
  10. Kinesin-8 Family
  11. Kinesin-10 Family
  12. Kinesin-13 Family
  13. Kinesin-14 Family
  14. Summary and Future Directions
  15. CONFLICT OF INTEREST DISCLOSURES
  16. REFERENCES