Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3sigma.
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.
Han
Baoguang
B
Department of Pharmacology and Toxicology, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Xie
Han
H
Chen
Qun
Q
Zhang
Jian-Ting
JT
D048948:14-3-3 Proteins; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells; D005092:Exonucleases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D005095:Exoribonucleases; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000494:pharmacology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011467:Prostate; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D008942:Mitoxantrone; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human