Advertisement

Tumor Biology

, Volume 37, Issue 7, pp 8799–8809 | Cite as

PIK3CA and PIK3CB silencing by RNAi reverse MDR and inhibit tumorigenic properties in human colorectal carcinoma

  • Shuhua Wu
  • Feifei Wen
  • Yangyang Li
  • Xiangqian Gao
  • Shuang He
  • Mengyao Liu
  • Xiangzhi Zhang
  • Dong Tian
Original Article

Abstract

Colorectal carcinoma (CRC) is the second most common and frequent cause of cancer-related deaths for men and women in the world. PIK3CA and PIK3CB that reverse multidrug resistance (MDR) can serve as predictive and prognostic markers as well as therapeutic targets for CRC treatment. In the present study, we showed that PIK3CA and PIK3CB are upregulated in CRCs and positively correlated with MDR-1, LRP, and GST-π. Long-term monitoring of 316 CRC patients showed that PIK3CA and PIK3CB were associated with poor survival time as shown by Kaplan-Meier analysis. Furthermore, we found that the downregulation of PIK3CA and PIK3CB reversed MDR; inhibited the capability of proliferation, migration, and invasion of CRC cells; and slowed down the CRC tumor growth in nude mice. Consistent with clinical observations, PIK3CA and PIK3CB significantly increase multidrug resistance of CRC cells in vivo. Together, these results suggest that PIK3CA and PIK3CB may be used as potential therapeutic drug targets for colorectal cancer.

Keywords

Colorectal cancer PIK3CA PIK3CB Stably transfected cell lines MDR Gene therapy 

Notes

Acknowledgments

This work was supported by the Scientific and Technological Project of Shandong Province.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Yokota J. Tumor progression and metastasis. Carcinogenesis. 2000;21:497–503.CrossRefPubMedGoogle Scholar
  2. 2.
    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Siegel R et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41.CrossRefPubMedGoogle Scholar
  4. 4.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  5. 5.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.CrossRefPubMedGoogle Scholar
  6. 6.
    Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.CrossRefPubMedGoogle Scholar
  8. 8.
    Rodriguez-Nieto S, Zhivotovsky B. Role of alterations in the apoptotic machinery in sensitivity of cancer cells to treatment. Curr Pharm Des. 2006;12:4411–25.CrossRefPubMedGoogle Scholar
  9. 9.
    Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, et al. miR-15b and miR-16 modulate multidrug resistance by targeting BCL-2 in human gastric cancer cell. Int J Cancer. 2008;123:372–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.CrossRefPubMedGoogle Scholar
  11. 11.
    Miura Y, Ohnami S, Yoshida K, Ohashi M, Nakano M, Fukuhara M, et al. Intraperitoneal injection of adenovirus expressing antisense K-ras RNA suppresses peritoneal dissemination of hamster syngeneic pancreatic cancer without systemic toxicity. Cancer Lett. 2005;218:53–62.CrossRefPubMedGoogle Scholar
  12. 12.
    Trujillo MA, Oneal MJ, Davydova J, Bergert E, Yamamoto M, Morris 3rd JC. Construction of an MUC-1 promoter driven, conditionally replicating adenovirus that expresses the sodium iodide symporter for gene therapy of breast cancer. Breast Cancer Res. 2009;11:R53.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Young LS, Searle PF, Onion D, Mautner V. Viral gene therapy strategies: from basic science to clinical application. J Pathol. 2006;208:299–318.CrossRefPubMedGoogle Scholar
  14. 14.
    Samuels Y et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.CrossRefPubMedGoogle Scholar
  15. 15.
    Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, Weiss W, et al. A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J. 2008;415:97–110.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A. 2008;105:13057–62.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cui B, Tao J, Yang Y. Studies on the expression patterns of class I PI3K catalytic subunits and its prognostic significance in colorectal cancer. Cell Biochem Biophys. 2012;62:47–54.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhu Y-F, Yu B-H, Li D-L, Ke H-L, Guo X-Z, Xiao X-Y. PI3K expression and PIK3CA mutations are related to colorectal cancer metastases. World J Gastroenterol. 2012;18(28):3745–51.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wen F, He S, Sun C, Li T, Wu S. PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma. Int J Clin Exp Pathol. 2014;7(11):8295–303.PubMedPubMedCentralGoogle Scholar
  20. 20.
    TANG H, LIU X, WANG Z, et al. Interaction of hsa-miR-381 and glioma suppressor LRRC4 is involved in glioma growth. Brain Res. 2011;1390:21–32.CrossRefPubMedGoogle Scholar
  21. 21.
    D’Incalci M. Adjuvant 5-FU based chemotherapy for colon cancer: match or miss the mismatch. Eur J Cancer. 2009;45(3):316–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Watanabe T. Chemoradiotherapy and adjuvant chemotherapy for rectal cancer. Int J Clin Oncol. 2008;13(6):488–97.CrossRefPubMedGoogle Scholar
  23. 23.
    Saseinul S, RBerardi R, SSalvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression amplification and NF-κB activation. Br J Can. 2008;98:71–6.CrossRefGoogle Scholar
  24. 24.
    Palumbo I, Piattoni S, Valentini V, Marini V, et al. Gefitinib enhances the effects of combined radiotherapy and 5-fluorouracil in a colorectal cancer cell line. Int J Color Dis. 2014;29:31–41.CrossRefGoogle Scholar
  25. 25.
    Kindler HL, Friberg G, Skoog L, Wade-Oliver K, Vokes EE. Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer. Am J Clin Oncol. 2005;28(4):340–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Mao C, Yang ZY, Hu XF, Chen Q, Tang JL. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2012;23:1518–25.CrossRefPubMedGoogle Scholar
  27. 27.
    Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. Clin Oncol. 2010;28:1254–61.CrossRefGoogle Scholar
  28. 28.
    Zheng T, Wang J, Chen X, Liu LX. Role of microRNA in anticancer drug resistance. Int J Cancer. 2009;126:2–10.CrossRefGoogle Scholar
  29. 29.
    Xie X, Tang B, Zhou J, Gao Q, Zhang P, et al. Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine. Oncol Rep. 2013;30:773–82.PubMedGoogle Scholar
  30. 30.
    Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, et al. Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 2008;99:121–8.PubMedGoogle Scholar
  31. 31.
    Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, et al. A drug targeting only p110α can block phosphoinositide 3-kinase signaling and tumour growth in certain cell types. Biochem J. 2011;438:53–62.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res. 2012;40:426–35.CrossRefPubMedGoogle Scholar
  33. 33.
    El-Readi MZ, Hamdan D, Farrag N, et al. Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines. Eur J Pharmacol. 2010;626:139–45.CrossRefPubMedGoogle Scholar
  34. 34.
    Barancík M, Bohácová V, Sedlák J, Sulová Z, Breier A. LY294,002, a specific inhibitor of PI3K/Akt kinase pathway, antagonizes P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci. 2006;29:426–34.CrossRefPubMedGoogle Scholar
  35. 35.
    Kuo MT, Liu Z, Wei Y, Lin-Lee YC, Tatebe S, Mills GB, et al. Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling. Oncogene. 2002;21:1945–54.CrossRefPubMedGoogle Scholar
  36. 36.
    García MG, Alaniz LD, Cordo Russo RI, Alvarez E, Hajos SE. PI3K/Akt inhibition modulates multidrug resistance and activates NF-kB in murine lymphoma cell lines. Leuk Res. 2009;33(2):288–96.CrossRefPubMedGoogle Scholar
  37. 37.
    Owonikoko TK, Khuri FR. Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am Soc Clin Oncol Educ Book. 2013;33:395–401.CrossRefGoogle Scholar
  38. 38.
    Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010;16:34–44.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Shuhua Wu
    • 1
  • Feifei Wen
    • 1
  • Yangyang Li
    • 1
  • Xiangqian Gao
    • 1
  • Shuang He
    • 1
  • Mengyao Liu
    • 1
  • Xiangzhi Zhang
    • 1
  • Dong Tian
    • 1
  1. 1.The Department of PathologyBinzhou Medical University HospitalBinzhouChina

Personalised recommendations