Targeted Inhibition of Phosphatidyl Inositol-3-kinase P110β, but Not P110α, Enhances Apoptosis and Sensitivity to Paclitaxel in Chemoresistant Ovarian Cancers

Overview

Journal Apoptosis

Publisher Springer

Date 2013 Feb 2

PMID 23371322

Citations 17

Authors

Ju-Yeon Jeong

Kyung-Sul Kim

Ji-Sook Moon

Ji-Ae Song

Sung-Ho Choi

Kwang-Il Kim

Tae-Heon Kim

Hee-Jung An

Affiliations

Soon will be listed here.

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the critical signaling cascades playing important roles in the chemoresistance of human cancer cells, including ovarian cancer. In this study, we investigated the potential of targeting the PI3K p110β-isoform as a novel approach to overcome the chemoresistance in ovarian cancer. The effects on apoptosis, cell viability, proliferation and migration in chemoresistant ovarian cancer cell were determined following targeted p110β inhibition by small interfering RNA (siRNA). Seven paclitaxel (PTX)-resistant sublines (SKpacs and A2780pac) were produced from SKOV3 and A2780 ovarian cancer cell lines. We, first, evaluated the expression of PI3K p110 isoforms in chemosensitive and chemoresistant ovarian cancer cell lines and patient specimens, and found that p110β-isoform was significantly overexpressed both in a panel of ovarian cancer samples, and in PTX-resistant sublines compared with their parent cell lines. RNA interference-mediated p110β silencing augmented PTX-mediated apoptosis (31.15 ± 13.88 %) and reduced cell viability (67 %) in PTX-resistant cells, whereas targeting p110α did not show a significant change in cell viability and apoptosis. In addition, p110β silencing impaired cell proliferation (60 %) in PTX-resistant SKpac cells. We also found the combined treatment group with p110β siRNA and PTX showed a significant inhibition of tumor growth of SKpac cells compared to the PTX-only treated group in a xenograft nude mouse model. Thus, the siRNA-mediated silencing of PI3K p110β resensitizes PTX-resistant ovarian cancer cells, and may be a useful therapeutic strategy for PTX-resistant ovarian cancers.

Citing Articles

Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options.

Nunes M, Bartosch C, Abreu M, Richardson A, Almeida R, Ricardo S Cells. 2024; 13(9.

PMID: 38727322 PMC: 11083313. DOI: 10.3390/cells13090786.

Mechanisms of Taxane Resistance.

Maloney S, Hoover C, Morejon-Lasso L, Prosperi J Cancers (Basel). 2020; 12(11).

PMID: 33182737 PMC: 7697134. DOI: 10.3390/cancers12113323.

Long Noncoding RNA TUG1 Promotes Autophagy-Associated Paclitaxel Resistance by Sponging miR-29b-3p in Ovarian Cancer Cells.

Gu L, Li Q, Liu H, Lu X, Zhu M Onco Targets Ther. 2020; 13:2007-2019.

PMID: 32189969 PMC: 7065918. DOI: 10.2147/OTT.S240434.

Improving the anti-keloid outcomes through liposomes loading paclitaxel-cholesterol complexes.

Wang M, Chen L, Huang W, Jin M, Wang Q, Gao Z Int J Nanomedicine. 2019; 14:1385-1400.

PMID: 30863067 PMC: 6390862. DOI: 10.2147/IJN.S195375.

Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the sirtuin 3-Forkhead box O3a axis in human small-cell lung cancer.

Wang X, Zeng Q, Li Z, Yang X, Xia W, Chen Z Thorac Cancer. 2019; 10(4):642-658.

PMID: 30779316 PMC: 6449276. DOI: 10.1111/1759-7714.12976.

References

Shayesteh L, Lu Y, Kuo W, Baldocchi R, Godfrey T, Collins C . PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999; 21(1):99-102. DOI: 10.1038/5042. View

Jamieson S, Flanagan J, Kolekar S, Buchanan C, Kendall J, Lee W . A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011; 438(1):53-62. PMC: 3174055. DOI: 10.1042/BJ20110502. View

Campbell I, Russell S, Choong D, Montgomery K, Ciavarella M, Hooi C . Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004; 64(21):7678-81. DOI: 10.1158/0008-5472.CAN-04-2933. View

Hu L, Hofmann J, Lu Y, Mills G, Jaffe R . Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 2002; 62(4):1087-92. View

McCubrey J, Steelman L, Abrams S, Lee J, Chang F, Bertrand F . Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006; 46:249-79. DOI: 10.1016/j.advenzreg.2006.01.004. View

Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee S . Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008; 454(7205):776-9. PMC: 2750091. DOI: 10.1038/nature07091. View

Guerreiro A, Fattet S, Fischer B, Shalaby T, Jackson S, Schoenwaelder S . Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration. Clin Cancer Res. 2008; 14(21):6761-9. DOI: 10.1158/1078-0432.CCR-08-0385. View

Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C . Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal. 2008; 1(36):ra3. PMC: 2694958. DOI: 10.1126/scisignal.1161577. View

Luque I, Gelinas C . Rel/NF-kappa B and I kappa B factors in oncogenesis. Semin Cancer Biol. 1997; 8(2):103-11. DOI: 10.1006/scbi.1997.0061. View

10.

Wang C, Mayo M, Korneluk R, Goeddel D, Baldwin Jr A . NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998; 281(5383):1680-3. DOI: 10.1126/science.281.5383.1680. View

11.

Foukas L, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E . Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature. 2006; 441(7091):366-70. DOI: 10.1038/nature04694. View

12.

Engelman J, Luo J, Cantley L . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006; 7(8):606-19. DOI: 10.1038/nrg1879. View

13.

Bookman M, Brady M, McGuire W, Harper P, Alberts D, Friedlander M . Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009; 27(9):1419-25. PMC: 2668552. DOI: 10.1200/JCO.2008.19.1684. View

14.

Liu P, Cheng H, Roberts T, Zhao J . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009; 8(8):627-44. PMC: 3142564. DOI: 10.1038/nrd2926. View

15.

Winograd-Katz S, Levitzki A . Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene. 2006; 25(56):7381-90. DOI: 10.1038/sj.onc.1209737. View

16.

Jiang B, Liu L . PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta. 2007; 1784(1):150-8. DOI: 10.1016/j.bbapap.2007.09.008. View

17.

Vivanco I, Sawyers C . The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002; 2(7):489-501. DOI: 10.1038/nrc839. View

18.

Liu S, Yu J, Yu H, Lv P, Chen H . Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells. Dig Liver Dis. 2006; 38(5):310-8. DOI: 10.1016/j.dld.2006.01.012. View

19.

Shen Y, Wang J, Yang T, Li Y, Jiang W, Guan Z . Platinums sensitize human epithelial tumor cells to lymphotoxin alpha by inhibiting NFkappaB-dependent transcription. Cancer Biol Ther. 2008; 7(9):1407-14. DOI: 10.4161/cbt.7.9.6429. View

20.

Stordal B, Pavlakis N, Davey R . A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship. Cancer Treat Rev. 2007; 33(8):688-703. DOI: 10.1016/j.ctrv.2007.07.013. View