SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell-cycle regulation, especially at the mitotic process stage, all of which favor cancer survival. Many studies on clinical specimens have shown that survivin expression is invariably up-regulated in human cancers and is associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. It is also reported that survivin inhibition, alone or in combination with the other therapies, induces or enhances apoptosis and mitotic catastrophe in tumor cells. Moreover, certain antitumor agents can reduce survivin expression. These findings suggest that survivin may be a promising molecular target against human malignancies. (Cancer Sci 2008; 99: 1709–1714)

Abbreviations:
AIF

apoptosis-inducing factor

IAP

inhibitor of apoptosis protein

P13K

phosphatidylinositol 3-kinase

siRNA

short interfering RNA

Originally identified as a member of the IAPs, survivin was discovered to play critical roles in cell division and cell survival.(1,2) Structurally, survivin contains a single BIR (baculoviral IAP repeats) domain, which is shared by other members of the IAPs, such as XIAP, c-IAP1, c-IAP2, and livin (Fig. 1).(3) This domain contributes to its function in apoptosis inhibition. However, instead of a carboxyl terminal RING finger shared by others, survivin contains an extended carboxyl-terminal alpha-helical coiled-coil which is thought to be important for its interaction with microtubules, hence its roles in cell division.(2,4) Functioning simultaneously at cell division and apoptosis inhibition, survivin obviously plays a pivotal role in determining cell survival.

image

Figure 1. Structure and functions of the survivin protein.

Download figure to PowerPoint

Cells are programmed to die when their existence is no longer required during development or when irreparable damage occurs. Survivin counteracts this process, along with other IAPs. Survivin blocks apoptosis induced by various stimuli including FAS/CD95,(5) irradiation,(6) and chemotherapeutic drugs, such as taxol(2) or staurosporine.(7) Inhibition of apoptosis is believed to be through direct binding to caspase-3 and caspase-7, preventing their activation.(5,8) Besides being a direct inhibitor for caspases, survivin can interact with Smac/DIABLO physically.(9) Survivin also provides cytoprotection to cells against caspase-independent cell death through the inhibition of the AIF pathway, which is known to induce caspase-independent DNA fragmentation.(10)

Survivin shows cell-cycle-dependent expression during cell division. Together with Aurora-B kinase, survivin forms as component of the chromosome passenger complex, which plays a role in chromosome segregation and cytokinesis in cell division.(11) Increased survivin expression is observed in the G2/M phase. The increase in survivin expression is believed to protect cells against a possible default induction of apoptosis in the case of aberrant mitosis.(2) Survivin is also required for the maintenance of the spindle assembly checkpoint to allow proper microtubule alignment to ensure cell propagation.(12)

Lack of survivin during cell division causes polyploidy as well as apoptosis(13) (Fig. 2). Polyploidy occurs following incomplete segregation or incomplete cytokinesis. The features of polyploidy are similar to that of mitotic catastrophe, which is also known as mitotic death, a form of nonapoptotic cell death, featuring the morphology of multinucleated giant cells.(14) They undergo slow or delayed cell death. Polyploidy cells after genotoxic stress express Rad51, a protein involved in the DNA damage repair mechanism, suggesting a possible selection or repair process in these cells.(15) Other factors, including the genome guardian, p53 protein and cell-cycle regulatory protein, p21waf1/cip1, also work together with survivin in response to DNA damage caused by anticancer agents.

image

Figure 2. Effect of inhibition of survivin.

Download figure to PowerPoint

In this review, we introduce the regulation and expression of survivin in human cancers, and we propose the possibility that survivin is a promising therapeutic target against human malignancies.

Survivin regulation

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

One of the mechanisms of survivin regulation is at the transcriptional level (Fig. 3). Survivin promoter activity is regulated through the β-catenin activated T-cell factor (TCF) transcription factor.(16) The expression of survivin is also Sp1-dependent, with transcriptional activity requiring two critical Sp1 sites.(17) Another report indicates that Sp1-mediated survivin expression is further subject to a p53-mediated transcriptional repression.(18) Other transcriptional regulation is mediated by Stat3.(19) Stat3 inhibitors down-regulate survivin in human breast and ovarian cancer cells.(20) However, we have reported that the Sp1 transcription factor, rather than Stat3, dominantly regulated promoter activity of survivin in esophageal cancer and gastric cancer; thus the regulation mode appears to be highly cell-type specific.(21) Hypoxia-inducible factor-1 alpha (HIF-1α) is another transcription factor involved in survivin regulation. Epidermal growth factor (EGF)–stimulated survivin up-regulation was mediated by HIF-1α in breast cancer cell lines.(22)

image

Figure 3. Survivin regulation at transcriptional and post-translational levels.

Download figure to PowerPoint

Survivin is a relatively short-lived protein (t1/2 at 30 min), regulated by proteasome degradation after polyubiquitination.(23) In addition of transcriptional level, the survivin protein becomes stable by phosphorylation of Thr34 by cdc2, which slows down clearance of survivin through the proteasome degradation.(24) Flavopiridol down-regulates survivin through inhibition of phosphorylation of Thr34.(25) Cyclin-dependent kinase inhibitor, NU6140, and paclitaxel combination also cause down-regulation of survivin through the inhibition of phosphorylation of Thr34 and enhanced caspase-dependent apoptosis in the HeLa cervical carcinoma cell line and an ovarian cell line.(26) Heat shock protein 90 (Hsp90), well known for its chaperone activity, has also been reported to regulate survivin. The disruption of survivin–Hsp90 interaction has been shown to result in the proteasome degradation of survivin, leading to mitotic defects and apoptosis.(27)

The Akt signaling pathway is also involved in survivin expression. Geranylgeranyltransferase I inhibitors (GGTIs) induce apoptosis in ovarian cancer cells by inhibition of the PI3K/AKT and survivin pathways.(28) A new class of anticancer drug, Trichostatin A (TCA), inhibitor of mammalian histone deacetylase (HDAC), also transiently induces survivin expression via activation of the EGFR/PI3K/Akt cell survival pathway.(29) Treatment of small cell lung cancer cells with cisplatin leads to up-regulation of survivin through the Akt survival pathway.(30)

Up-regulation of survivin in human malignancies

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

Survivin is expressed in embryonic and fetal tissues, but is almost undetectable in adult tissues.(1,3) However, overexpression of survivin has been reported in almost all human malignancies including lung cancer, breast cancer; stomach, esophagus, liver, and ovary cancers; and brain and hematological cancers.(1,31) Based on detection of protein by immunohistochemistry and mRNA by polymerase chain reaction techniques, overexpression of survivin has been reported in various human malignancies (Table 1(32–45)). Similar to its expression, survivin promoter activity is largely silent in normal cell types, but is increased in tumor cell lines.(46)

Table 1. Survivin protein or mRNA expression in human cancers
CancerExpressionRef No.
Esophageal cancer80%(32)
Gastric cancer34.5~68%(33,34)
Colorectal cancer63.5%(35)
Pancreatic cancer76.9~88%(36,37)
Hepatocellular cancer41~87%(38,39)
Breast cancer70.7~90.2%(40,41)
Ovarian cancer73.5%(42)
Lung cancer85.5%(43)
Bladder cancer57.8%(44)
Acute myeloid leukemia54.8%(45)
Acute lymphocytic leukemia68.8%(45)

The specific up-regulation of survivin in cancer cells is further supported by the immunological responses detected against it. Survivin-specific CD8+ T-cell-mediated and CD4+ cell-mediated immune response have been identified in the peripheral blood of colorectal cancer patients.(47) Cytotoxic T-lymphocyte response to survivin has also been detected in breast, melanoma, and chronic lymphatic leukemia patients.(48) Induction of survivin-specific immune response has been confirmed in vitro.(49)

Cancer cells thus seem to utilize the cytoprotective character of survivin to ensure its continual progression. During colorectal carcinogenesis, the expression of survivin was found to increase from adenoma with low-grade dysplasia (2.3%) to high-grade dysplasia (52.4%) to carcinoma in adenoma (63.3%).(50) Similar results has been found in the tumorigenesis of pancreatic ductal adenocarcinoma. While no expression has been found in normal pancreatic ducts, survivin expression steadily increased from low-grade pancreatic intraepithelial neoplasia to high-grade lesions and to the highest in pancreatic ductal adenocarcinoma tissues.(51) A study on ovarian cancer has also reported that survivin expression increased from benign tumors (21.2%) to borderline tumors (47.8%) to ovarian carcinomas (51.1%).(52) Furthermore, most reports have suggested consistencies with a reduced apoptotic index(53) indicating a survival advantage in these tumor cells.

Survivin expression has been shown to induce a global transcriptional change in the tumor microenvironment that may promote tumor progression. In addition to the survival of cancer cells, survivin has been implicated in angiogenesis. Molecular targeting of survivin has led to not only inhibition of tumor growth, but also reduction in tumor-derived blood vessels.(54) Survivin has also showed a cytoprotection effect, possibly mediated by PI3K pathways, on endothelial cells, which is mediated by VEGF.(55)

Association between survivin expression and prognosis or therapy resistance

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

Survivin expression in most cancers is associated with patients’ survival or disease recurrence, and resistance to chemotherapy or radiotherapy. A higher survivin expression has been correlated with an unfavorable survival or disease recurrence in colorectal cancer, particularly in stage II disease(35) in esophageal cancer,(56) hepatocellular carcinoma,(38) lung cancer,(43) glioma,(53) leukemia,(45) and other cancer types. Survivin has been further identified as an independent prognosis factor in multivariate analysis in different patient groups. With regard to chemosensitivity, patients with lower survivin expression were more responsive to preoperative chemotherapy with 5-flourouracil and cisplatin in esophageal cancer.(57) Overexpression of survivin was also associated with clinical resistance to a taxol-based regimen for ovarian carcinomas.(58) It is also reported that patients with lower survivin expression in pretreatment biopsies were more responsive to radiotherapies in rectal cancer.(59) Taken together, these findings suggest that diminution of the basal survivin expression in tumor cells would increase sensitivity to cancer therapies.

Modulation of survivin by anticancer drugs

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

The above evidence in clinics indicates that overexpression of survivin in cancer invariably provides a survival advantage in tumor cells. Therefore, lack of survivin or disruption of the survivin function would cause cell death such as apoptosis and mitotic catastrophe in these cells. In fact, many anticancer drugs currently in use in clinics as well as those still undergoing testing are reportedly shown to have inhibitory effects on survivin. (i) Celecoxib and its derivatives have been shown to down-regulate survivin in a wide range of tumor cells, including glioblastoma; lymphoma; multiple myeloma; and carcinoma of the breast, colon and prostate, inducing apoptosis.(60) (ii) COX-2 inhibitor etodolac and oxaliplatin have been shown to significantly down-regulate survivin in human colon cancer cells, causing growth inhibition and cell death.(61) (iii) Silibilin derivatives, such as Silymarin, which have showed efficacy toward prostate cancer, have also been shown to down-regulate survivin.(62) (iv) Tetra-O-methyl nordihydroguaiaretic acid (a small organic compound with antitumor activity) has been shown to selectively target survivin and cdc2, both Sp1-regulated proteins that control apoptosis and the cell cycle. Reintroduction of survivin inhibited apoptosis.(63) (v) Proteasome inhibitor (MG132 or MG115) has been shown to down-regulate survivin in hepatocellular carcinoma cell lines.(64) (vi) Other novel therapeutic approaches using small molecule inhibitors, nucleoside analogs,(65) or natural products or components such as betulinic acid(66) indole-3-carbinol, found in vegetables,(67) have demonstrated anticancer effects, and also been shown to down-regulate survivin after treatment in certain cell lines used in respective studies.

In the meantime, while survivin is down-regulated by most anticancer drugs, up-regulations following treatment regimens have been previously reported. Treatment by taxol, adriamycin, or ultraviolet B irradiation in breast cancer MCF-7 and cervical cancer HeLa cells have resulted in a four- to five-fold increase in survivin expression, possibly by activation of Thr34 phosphorylation as mentioned above.(68) Exposure of cells to radiation or photodynamic therapy similarly caused up-regulation of survivin.(69) Cisplatin has also led to up-regulation of survivin through the Akt survival pathway in small cell lung cancer cells.(30) Supposedly these could be responses for tumor cells to survive in resistance to the various toxic stresses.

Therapeutic approaches

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

Similar to the conserved mechanism in the developmental process, survivin inhibition has been shown to enhance cell death.(3) Various approaches have been attempted to down-regulate or block survivin in cancer cells to inhibit cell survival and at the same time enhance cell death.

Inhibition of survivin by the molecular approach.

  • Molecular antagonist utilizing antisense, siRNA, ribozyme, dominant-negative mutants have shown satisfactory results. An approach using short hairpin RNA (shRNA) successfully reduced survivin expression, and induced apoptosis and growth inhibition in a lymphoma cell line.(70) Ribozyme-mediated inhibition of survivin induced polyploidy and caspase-9-dependent apoptosis in prostate cancer cells.(71) We have shown that siRNA against survivin induced drastic induction of mitotic catastrophe in esophageal cancer cells (Fig. 4). A therapeutic approach using survivin responsive conditionally replicating adenovirus displayed tumor cell specificity, induced tumor cell death and inhibition of tumor growth,(72) and also sensitized human melanoma cells to gamma irradiation.(73) Replication-deficient adenovirus encoding a survivin mutant caused massive apoptosis in tumor cells but had no effect on proliferation normal cells.(74)

image

Figure 4. Survivin inhibition caused mitotic catastrophe. Short interfering RNA (siRNA) against survivin down-regulated survivin protein expression, inducing mitotic catastrophe in an esophageal squamous cell carcinoma cell line, TE8. The arrows indicate multinucleated giant cells compatible with mitotic catastrophe. Similar phenomena have been observed in other gastrointestinal cancer cell lines.(21)

Download figure to PowerPoint

Other treatments plus survivin inhibition.  Survivin inhibition by molecular techniques has been shown to increase the sensitivity of cells to chemotherapeutic drugs, melanoma cells to cisplatin treatment,(75) lung cancer cells to adriamycin treatment,(76) and prostate cancer cells to paclitaxel.(77) Inhibition of survivin by siRNA also increased the sensitivity of colorectal and pancreatic cancer cells to radiation therapy.(59,78) Combination use of siRNA against survivin and heat shock protein, Hsp90 inhibitor 17-allylamino-17-demethoxygeldamycin (17-AAG), reduced cell proliferation and enhanced apoptosis.(79) In addition, shepherdin, an antagonist against interaction between Hsp90 and survivin, induced massive death of tumor cells through apoptotic and nonapoptotic mechanisms.(80)

Combination therapy with survivin inhibitors and other treatment.  Since various anticancer drugs can reduce survivin levels in tumor cells, they may enhance efficacy of the other chemotherapy or radiotherapy treatments. During investigation into why oxaliplatin can enhance the efficacy of other anticancer drugs, we have found that oxaliplatin was a potent inhibitor of survivin in colon cancer cells(81) (Fig. 5a), and also in other gastrointestinal tumor cells.(21,82) On the hand, taxol causes cell arrest in mitosis with increased expression of survivin.(68) To our interest, oxaliplatin in combination with taxol displayed a synergic growth inhibition that could be attributable to drastic mitotic catastrophe (Fig. 5b,c). In such a combination treatment, survivin was not enhanced enough compared to inducement by taxol alone (Fig. 5d). Therefore, we postulate that down-regulation of survivin by oxaliplatin may be one of the events involved in the synergic mechanism. These findings suggest that certain agents (e.g. oxaliplatin) that decrease survivin expression may considerably influence the effectiveness of the other treatment, possibly by breaking the balance for cell survival signaling. This notion should be applicable to radiation therapy in combination with oxaliplatin, as a survivin inhibitor. However, we should emphasize that the combination of survivin inhibitors with mitotic inhibitors, such as taxol, might be more effective than with other antitumor drugs that arrest the cells at G1 phase, taking into account the essential role of survivin in mitosis. This issue should be further addressed in the future.

image

Figure 5. (a) Oxaliplatin induced survivin down-regulation in colon cancer cells. (b) Combination treatment of oxaliplatin and taxol displayed a synergistic effect on SW480 colon cell growth. (c) Increased cells undergoing mitotic catastrophe were observed in combination treatment group. (d) Oxaliplatin withdrew taxol-induced survivin up-regulation.

Download figure to PowerPoint

Also, the mechanisms underlying the down-regulation of survivin levels by oxaliplatin should be clarified. We suggest two mechanisms, that is, Sp1 down-regulation (Fig. 6a–c) and proteasome degradation (Fig. 6d), which can mediate survivin inhibition after oxaliplatin treatment, at least in certain gastrointestinal cell lines.

image

Figure 6. Survivin regulation by oxaliplatin via Sp1-inactivation and proteasome-mediated degradation. (a) Survivin promoter activity in esophageal TE7 cells after treatment with oxaliplatin. Oxaliplatin significantly reduced survivin promoter activity. (b) Sp1 expression at 48 h after oxaliplatin treatment. Sp1 expression decreased in oxaliplatin-treated cells compared to untreated controls. (c) Effect of Sp1 inhibitor (Mithramycin A) on survivin-promoter activity at 24 h after transfection. Mithramycin A inhibited survivin promoter activity. (d) Proteasome-mediated degradation. Effects of a proteasome inhibitor (lactacystin) on survivin expression following oxaliplatin treatment. Down-regulation of survivin expression after oxaliplatin treatment was partly rescued by the addition of the lactacystin. These events (a–d) were observed in several gastrointestinal cancer cells (data not shown).

Download figure to PowerPoint

Targeting overexpression of survivin.  Invariably high and specific survivin expression in various human cancers makes it an optimal therapeutic target. Utilizing a fusion of the survivin gene promoter to the coding sequence of active granzyme B has led to increased expression of granzyme B in tumor cells, resulting in a higher rate of apoptotic cell death.(83) Similar approaches utilizing survivin promoter-driven siRNA targeting human telomerase reverse transcriptase (hTERT) and stathmin were also successful in increasing radiosensitization and growth inhibition, respectively.(84,85)

Immunological approaches using vaccine have also been developed. Vaccine utilizing survivin antigenic peptide, DNA-based vaccine, as well as dendritic cells loaded with survivin protein, has demonstrated promising results in inducing cytotoxic T-lymphocyte (CTL) response, leading to effective eradication of tumor cells in animal models or patients in clinical trials.(86–88) A patient was reported to achieve complete remission of liver metastasis of pancreatic cancer following treatment with survivin vaccine.(89) Further validation of survivin as a target for cancer treatment will be dependent on the outcomes of clinical studies.

Conclusion

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References

Survivin is one of the highly conserved proteins that are indispensable for cell survival in development. Survivin is repressed or down-regulated in most normal adult tissues; hence its up-regulation in cancers could make it a highly specific target. The majority of anticancer drugs, although mediated through different regulatory pathways in different types of cancers, lead to down-regulation of survivin, which causes cell death through apoptosis or mitotic catastrophe. Up-regulation of survivin by others nevertheless suggests possible mechanisms of compensation to assure cell survival in certain cells. Inhibition of survivin with novel molecular genetic approaches in combination with the use of chemotherapeutic drugs or radiotherapy may improve some of the current regimen. Although survivin is a potential target for therapeutic purposes, the approaches nevertheless should be carefully designed, considering the possibility of hindering its normal functions in limited adult tissues, such as hematopoietic cells. Further investigation is thus necessary to understand the complex cellular circuitry of survivin in cancer as well as in physiological conditions.

References

  1. Top of page
  2. Abstract
  3. Survivin regulation
  4. Up-regulation of survivin in human malignancies
  5. Association between survivin expression and prognosis or therapy resistance
  6. Modulation of survivin by anticancer drugs
  7. Therapeutic approaches
  8. Conclusion
  9. References