Annals of Surgical Oncology

, Volume 18, Issue 2, pp 580–588 | Cite as

mTOR Signaling is Involved in Indomethacin and Nimesulide Suppression of Colorectal Cancer Cell Growth via a COX-2 Independent Pathway

  • Yan-Jie Zhang
  • Yu-Jie Bao
  • Qiang Dai
  • Wen-Yan Yang
  • Peng Cheng
  • Li-Ming Zhu
  • Bi-Jun Wang
  • Fo-Hu Jiang
Translational Research and Biomarkers

Abstract

Background

Inhibition of mammalian target of rapamycin (mTOR) represents an attractive target for anticancer therapy, but its role in suppression of colorectal cancer (CRC) cell growth by cyclooxygenase-2 (COX-2) inhibitors is unclear. Here, we analyzed the effect of indomethacin (Indo, a nonselective COX-2 inhibitor) and nimesulide (Nim, a selective COX-2 inhibitor) on mTOR signaling in CRC cells in vitro and in vivo to determine the dependence of this effect on COX-2.

Methods

Human CRC cell lines with varying COX-2 expression levels were treated with Indo and Nim. Western blot test was performed to detect mTOR-related components (mTOR, p70s6 K, and 4EBP1), and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW1116 cells were injected into athymic nude mice to establish a CRC xenograft model. After treatment with Nim, tumor volume, mTOR signaling, and apoptosis were evaluated in this model. HT29 and SW1116 cells were also treated with Nim after transfection with COX-2-specific small interfering RNA (siRNA) to assess dependence of COX-2 on mTOR signaling under drug treatment.

Results

Both Indo and Nim reduced mTOR signaling activity in CRC cells that differ in their COX-2 expression in vitro and in vivo. Additionally, Indo and Nim could reduce the mTOR signaling activity after COX-2 silencing in CRC cells.

Conclusions

mTOR signaling is involved in Indo- and Nim-mediated suppression of CRC growth via a COX-2 independent pathway. This study unveils a novel mechanism through which COX-2 inhibitors exerts their anticancer effects and further emphasizes targeting mTOR signaling in anticancer therapy.

Notes

Acknowledgment

This work was supported by grants from the National Natural Science Foundation of China (30900672) and Shanghai Rising Star Program (10QA1404300) to Y.J.Z. and grants from the Shanghai Municipal Education Commission (jdy09074) to Y.J.B.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Tsang CK, Zheng XF. TOR-in(g) the nucleus. Cell Cycle. 2007;6:25–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.CrossRefPubMedGoogle Scholar
  3. 3.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today. 2007;12:112–24.CrossRefPubMedGoogle Scholar
  5. 5.
    Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. Semin Oncol. 2009;36(Suppl 3):S3–17.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang YJ, Dai Q, Tian XQ, et al. mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol. 2009;16:2617–28.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang YJ, Tian XQ, Sun DF, et al. Combined inhibition of MEK and mTOR signaling inhibits initiation and progression of colorectal cancer. Cancer Invest. 2009;27:273–85.CrossRefPubMedGoogle Scholar
  8. 8.
    Sarkar FH, Adsule S, Li Y, Padhye S. Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007;7:599–608.CrossRefPubMedGoogle Scholar
  9. 9.
    Grösch S, Maier TJ, Schiffmann S, Geisslinger G. Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst. 2006;98:736–47.CrossRefPubMedGoogle Scholar
  10. 10.
    Kashfi K, Rigas B. Non-COX-2 targets and cancer: expanding the molecular target repertoire of chemoprevention. Biochem Pharmacol. 2005;70:969–86.CrossRefPubMedGoogle Scholar
  11. 11.
    Jana NR. NSAIDs and apoptosis. Cell Mol Life Sci. 2008;65:1295–301.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghosh M, Wang H, Ai Y, et al. COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation. J Exp Med. 2007;204:2053–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Yamauchi T, Watanabe M, Hasegawa H, et al. The potential for a selective cyclooxygenase-2 inhibitor in the prevention of liver metastasis in human colorectal cancer. Anticancer Res. 2003;23:245–9.PubMedGoogle Scholar
  14. 14.
    Zhang YJ, Dai Q, Wu SM, et al. Susceptibility for NSAIDs-induced apoptosis correlates to p53 gene status in gastric cancer cells. Cancer Invest. 2008;26:868–77.CrossRefPubMedGoogle Scholar
  15. 15.
    Czembirek C, Eder-Czembirek C, Erovic BM, et al. The cyclooxygenase-2 inhibitor nimesulide, a nonsteroidal analgesic, decreases the effect of radiation therapy in head-and-neck cancer cells. Strahlenther Onkol. 2009;185:310–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Shaik MS, Chatterjee A, Singh M. Effect of a selective cyclooxygenase-2 inhibitor, nimesulide, on the growth of lung tumors and their expression of cyclooxygenase-2 and peroxisome proliferator- activated receptor-gamma. Clin Cancer Res. 2004;10:1521–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang YJ, Zhao SL, Tian XQ, et al. Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer. Int J Colorectal Dis. 2009;24:629–39.CrossRefPubMedGoogle Scholar
  18. 18.
    Hiraga T, Myoui A, Choi ME, Yoshikawa H, Yoneda T. Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-beta enhances bone metastases in breast cancer. Cancer Res. 2006;66:2067–73.CrossRefPubMedGoogle Scholar
  19. 19.
    Parashar B, Shafit-Zagardo B. Inhibition of human neuroblastoma in SCID mice by low-dose of selective Cox-2 inhibitor nimesulide. J Neurooncol. 2006;78:129–34.CrossRefPubMedGoogle Scholar
  20. 20.
    Makowski M, Grzela T, Niderla J, et al. Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice. Clin Cancer Res. 2003;9:5417–22.PubMedGoogle Scholar
  21. 21.
    Menon S, Manning BD. Common corruption of the mTOR signaling network in human tumors. Oncogene. 2008;27(Suppl 2):S43–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Sudarsanam S, Johnson DE. Functional consequences of mTOR inhibition. Curr Opin Drug Discov Devel. 2010;13:31–40.PubMedGoogle Scholar
  23. 23.
    Dancey JE, Curiel R, Purvis J. Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. Semin Oncol. 2009;36(Suppl 3):S46–58.CrossRefPubMedGoogle Scholar
  24. 24.
    Singleton PA, Mambetsariev N, Lennon FE, et al. Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. J Angiogenes Res. 2010;2:5.Google Scholar
  25. 25.
    Efferson CL, Winkelmann CT, Ware C, et al. Downregulation of Notch pathway by a γ-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. Cancer Res. 2010;70:2476–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology. 2003;38:756–68.CrossRefPubMedGoogle Scholar
  27. 27.
    Ladu S, Calvisi DF, Conner EA, et al. E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer. Gastroenterology. 2008;135:1322–32.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2010

Authors and Affiliations

  • Yan-Jie Zhang
    • 1
  • Yu-Jie Bao
    • 1
  • Qiang Dai
    • 1
  • Wen-Yan Yang
    • 1
  • Peng Cheng
    • 1
  • Li-Ming Zhu
    • 1
  • Bi-Jun Wang
    • 1
  • Fo-Hu Jiang
    • 1
  1. 1.Department of DigestionNo. 3 People’s Hospital Affiliated to Shanghai Jiaotong University, School of MedicineShanghaiChina

Personalised recommendations