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Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3sigma
Baoguang Han1, Han Xie, Qun Chen
1Department of Pharmacology and Toxicology, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract:
Advanced and hormone-refractory prostate cancer has long been considered as a chemoresistant disease. Recently, it was found that 14-3-3sigma expression increases as prostate tumor progresses, and that 14-3-3sigma contributes significantly to drug resistance in breast cancers. We, thus, hypothesized that advanced and hormone-refractory prostate cancers may have an increased level of 14-3-3sigma, which in turn may contribute to drug resistance in advanced and hormone-refractory prostate cancers. In this study, we tested this hypothesis and found that, indeed, the expression level of 14-3-3sigma in androgen-independent prostate cancer cell lines DU145, PC3, and CWR22RV are much higher than that in the androgen-dependent cell line LNCaP, and that the androgen-independent cells are more resistant to mitoxantrone and Adriamycin than the androgen-dependent cells. Depleting 14-3-3sigma expression in DU145 and CWR22RV by RNA interference significantly sensitized these cells to mitoxantrone and Adriamycin by abrogating G2-M checkpoint and increasing apoptosis, whereas restoring 14-3-3sigma expression in LNCaP cells enhanced drug resistance. We also showed that 14-3-3sigma deficiency caused nuclear localization of Cdc2 and dephosphorylation of the Tyr15 residue upon DNA damage. Based on these studies, we propose that therapeutic intervention targeting 14-3-3sigma may be useful for sensitizing hormone-refractory prostate cancers to chemotherapy by both G2-M checkpoint abrogation and apoptosis enhancement.
Insights
Advanced prostate cancer is resistant to chemotherapy, partly due to increased 14-3-3sigma protein. Reducing 14-3-3sigma may sensitize tumors to chemotherapy by enhancing apoptosis and overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Advanced and hormone-refractory prostate cancer (PCa) is largely chemoresistant.
- Increased 14-3-3sigma expression correlates with tumor progression and drug resistance in breast cancer.
Purpose of the Study:
- To investigate the role of 14-3-3sigma in chemoresistance of advanced prostate cancer.
- To test the hypothesis that elevated 14-3-3sigma contributes to drug resistance in hormone-refractory PCa.
Main Methods:
- Compared 14-3-3sigma expression in androgen-dependent and -independent prostate cancer cell lines.
- Assessed chemoresistance to mitoxantrone and Adriamycin.
- Utilized RNA interference to deplete 14-3-3sigma and analyzed cell cycle (G2-M checkpoint) and apoptosis.
- Restored 14-3-3sigma expression in LNCaP cells.
Main Results:
- Androgen-independent PCa cell lines (DU145, PC3, CWR22RV) exhibited higher 14-3-3sigma levels than androgen-dependent LNCaP cells.
- Androgen-independent cells showed greater resistance to mitoxantrone and Adriamycin.
- Depleting 14-3-3sigma sensitized cells to chemotherapy by abrogating the G2-M checkpoint and increasing apoptosis.
- Restoring 14-3-3sigma enhanced drug resistance in LNCaP cells.
- 14-3-3sigma deficiency led to nuclear Cdc2 localization and Tyr15 dephosphorylation upon DNA damage.
Conclusions:
- Elevated 14-3-3sigma expression contributes to chemoresistance in hormone-refractory prostate cancer.
- Targeting 14-3-3sigma may represent a therapeutic strategy to sensitize prostate cancer to chemotherapy by modulating the G2-M checkpoint and apoptosis.
