SEARCH

SEARCH BY CITATION

Obesity not only results in increased incidence but also leads to poor prognosis of many cancers. The increased cancer incidence in obesity is accounted for by the activation of cellular signal pathways which are carcinogenic such as Src/PI3K/Akt pathway [Chen, 2008; Huang and Chen, 2009b]. However, the mechanism for the poor prognosis in obesity-associated cancer is still unclear. It is an urgent issue required to be solved so that the treatment of obesity-associated cancer can be improved. A possible explanation is that the poor prognosis in obesity-associated cancer is caused by decreased drug efficacy due to the activation of multiple cellular signal pathways. Among these pathways the Src/PI3K/Akt may play a critical role. It is well demonstrated that the Src/PI3K/Akt pathway is activated by multiple cancer risk factors in obesity, while the activation of the pathway has also been shown to associate with decreased drug efficacy. Thus, it will be interesting to further demonstrate the critical role of the pathway in decreased drug efficacy caused by obesity and confirm that the activation of the pathway has lead to poor prognosis in obesity-associated cancer.

EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES

There are many evidences that obesity can cause poor prognosis of many cancers such as ovarian cancer, leukemia, papillary thyroid cancer, and colon cancer [Dignam et al., 2006; Uddin et al., 2010]. Epidemic studies showed that severe obesity (BMI >35 kg/m2) caused increased mortality and recurrence of colon cancer [Dignam et al., 2006; Jacobs et al., 2007]. However, it has not been studied if this is related with PI3K and drug efficacy. Obesity has also been shown to lead to poor prognosis in ovarian cancer. Uddin et al. 2009 showed that there is correlation between the poor prognosis of ovarian cancer and the activation of leptin pathway. The increased expression of leptin receptor caused the activation PI3K/Akt which plays a key role in the poor prognosis. However, if it is associated with decreased drug efficacy is not studied. In leukemia, obesity is demonstrated to increase and drug resistance leading to poor prognosis [Behan et al., 2009]. In vitro experiment showed that adipocytes increased drug resistance in the treatment of leukemia. It is not known if it is via PI3K/Akt pathway.

ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES

The Src/PI3K/Akt pathway is highly activated by multiple cancer risk factors which are elevated in obesity [Jaffe and Schwartz, 2008; Huang and Chen, 2009b]. These factors include increased blood levels of insulin, IGF-1, leptin, TNF-alpha, and IL-6. These factors have been demonstrated to activate Src/PI3K/Akt to promote carcinogenesis [Jaffe and Schwartz, 2008; Roberts et al., 2009; Huang and Chen, 2009b]. In addition, decreased blood level of adiponectin in obesity also contributes to the action of the pathway as adiponectin can block insulin and leptin [Fujisawa et al., 2008; Huang and Chen, 2009a]. Recently, IL23/17 has also been shown to be activated in obesity which in turn activates the Src/PI3K/Akt pathway [Hsieh et al., 2002; Sumarac-Dumanovic et al., 2009].

THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES

Src has been demonstrated to be responsible for inherent and acquired oxaliplatin resistance in colon cancer and the inhibition of Src by dasatinib has been shown to synergize the effect of oxaliplatin [Kopetz et al., 2009]. In human renal cancer cells, the activation of the PI3K/Akt has been demonstrated to increase the cancer cells resistant to oxaliplatin [Kim et al., 2008b]. Evidence also showed that the activation of the PI3K/Akt pathway increases resistance to cisplatin in ovarian cancer cell line [Lee et al., 2005]. The down-stream of the Src/PI3K/Akt pathways Bcl2, Bad, and Pim have also been associated with decreased drug efficacy caused by isolated adipocytes from obesity [Behan et al., 2009]. However, to fully understand the mechanism of decreased drug efficacy in obesity, it may be necessary to test the change of the Src/PI3K/Akt pathway caused by adipocytes.

THERAPEUTIC IMPLICATIONS

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES

Due to the important role of the Src/PI3K/Akt in the decreased drug efficacy in obesity-associated cancer, the inhibition of the signal pathway may have clinical implication. The use of the inhibitors of the pathway may overcome the decreased drug efficacy. It could have synergistic effect with chemotherapy drugs. It has been demonstrated in cholangiocarcinoma cells, the inhibition of PI3K increased oxaliplatin cytotoxicity [Leelawat et al., 2009]. In colon cancer, inhibition of PI3K has also been shown to increase the cytotoxicity of low dose of BBR3610 [Mitchell et al., 2007]. Inhibition of the down-stream protein of the Src/PI3K/Akt pathway bcl2 by sanguinarine caused apoptosis and sensitize the TRIAL-mediated apoptosis in breast cancer cells [Kim et al., 2008a].

CONCLUSIONS

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES

In conclusion, a possible explanation for poor prognosis of obesity-associated cancer is activation of the Src/PI3K/Akt by multiple cancer risk factors like insulin, IGF-1, leptin, IL-6, IL-17, IL-23, TNF-alpha, which in turn reduces chemotherapy efficacy. Inhibition of the Src/PI3K/Akt pathway should have therapeutic implications to improve the treatment of obesity-associated colon cancer and warrant further study.

REFERENCES

  1. Top of page
  2. EVIDENCE FOR THE POOR PROGNOSIS OF OBESITY-ASSOCIATED CANCER
  3. ACTIVATION OF THE SRC/PI3K/AKT SIGNAL PATHWAY IN OBESITY
  4. THE ROLE OF THE SRC/PI3K/AKT PATHWAY IN DECREASED DRUG EFFICACY
  5. THERAPEUTIC IMPLICATIONS
  6. CONCLUSIONS
  7. REFERENCES
  • Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Moses AS, Avramis VI, Louie SG, Butturini A, Heisterkamp N, Mittelman SD. 2009. Adipocytes impair leukemia treatment in mice. Cancer Res 69(19): 78677874.
  • Chen J. 2008. Is Src the key to understanding metastasis and developing new treatments for colon cancer? Nat Clin Pract Gastroenterol Hepatol 5(6): 306307.
  • Dignam JJ, Polite BN, Yothers G, Raich P, Colangelo L, O'Connell MJ, Wolmark N. 2006. Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98(22): 16471654.
  • Fujisawa T, Endo H, Tomimoto A, Sugiyama M, Takahashi H, Saito S, Inamori M, Nakajima N, Watanabe M, Kubota N, Yamauchi T, Kadowaki T, Wada K, Nakagama H, Nakajima A. 2008. Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut 57(11): 15311538.
  • Hsieh HG, Loong CC, Lin CY. 2002. Interleukin-17 induces src/MAPK cascades activation in human renal epithelial cells. Cytokine 19: 159174.
  • Huang XF, Chen J. 2009a. Adiponectin and signal pathways in obesity-induced colon cancer: Comment on “adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition.” Gut 58(8): 1169.
  • Huang XF, Chen J. 2009b. Obesity, the PI3K/Akt signal pathway and colon cancer. Obes Rev 10(6): 610616.
  • Jacobs ET, Martínez ME, Alberts DS, Jiang R, Lance P, Lowe KA, Thompson PA. 2007. Association between body size and colorectal adenoma recurrence. Clin Gastroenterol Hepatol 5(8): 982990.
  • Jaffe T, Schwartz B. 2008. Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways. Int J Cancer J Int Cancer 123(11): 25432556.
  • Kim S, Lee TJ, Leem J, Choi KS, Park JW, Kwon TK. 2008a. Sanguinarine-induced apoptosis: Generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL. J Cell Biochem 104(3): 895907.
  • Kim S, Lee TJ, Park JW, Kwon TK. 2008b. Overexpression of cFLIPs inhibits oxaliplatin-mediated apoptosis through enhanced XIAP stability and Akt activation in human renal cancer cells. J Cell Biochem 105(4): 971979.
  • Kopetz S, Lesslie DP, Dallas NA, Park SI, Johnson M, Parikh NU, Kim MP, Abbruzzese JL, Ellis LM, Chandra J, Gallick GE. 2009. Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 69(9): 38423849.
  • Lee S, Choi EJ, Jin C, Kim DH. 2005. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 97(1): 2634.
  • Leelawat K, Narong S, Udomchaiprasertkul W, Leelawat S, Tungpradubkul S. 2009. Inhibition of PI3K increases oxaliplatin sensitivity in cholangiocarcinoma cells. Cancer Cell Int 9(3).
  • Mitchell C, Kabolizadeh P, Ryan J, Roberts JD, Yacoub A, Curiel DT, Fisher PB, Hagan MP, Farrell NP, Grant S, Dent P. 2007. Low-dose BBR3610 toxicity in colon cancer cells is p53-independent and enhanced by inhibition of epidermal growth factor receptor (ERBB1)-phosphatidyl inositol 3 kinase signaling. Mol Pharmacol 72(3): 704714.
  • Roberts DL, Dive C, Renehan AG. 2009. Biological mechanisms linking obesity and cancer risk: New perspectives. Annu Rev Med 61: 301316.
  • Sumarac-Dumanovic M, Stevanovic D, Ljubic A, Jorga J, Simic M, Stamenkovic-Pejkovic D, Starcevic V, Trajkovic V, Micic D. 2009. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes (Lond) 33(1): 151156.
  • Uddin S, Bu R, Ahmed M, Abubaker J, Al-Dayel F, Bavi P, Al-Kuraya KS. 2009. Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer. Mol Cancer 8(74).
  • Uddin S, Bavi P, Siraj A, Ahmed M, Al-Rasheed M, Hussain A, Ahmed M, Amin T, Alzahrani A, Al-Dayel F, Abubaker J, Bu R, Al-Kuraya K. 2010. Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma. Endocr Relat Cancer 17(1): 191202.