Calcitonin induces apoptosis resistance in prostate cancer cell lines against cytotoxic drugs via the Akt/survivin pathway.
The expression of calcitonin (CT) and CT-receptor (CTR) mRNA in primary prostate tumors increase with tumor progression. Since advanced prostate tumors display chemoresistance, we tested a hypothesis that CT increases apoptosis resistance of prostate cells against cytotoxic drugs. We examined the effect of CT on etoposide-induced apoptosis in PC-3M, LNCaP and NRP-152 cell lines. The cytoprotective actions of CT were then tested on paclitaxel-, dexamethasone- and selenite-induced apoptosis. We also examined cytotoxic actions of these drugs in CTR-silenced PC-3M cells. Since the role of Akt and inhibitors of apoptosis proteins (IAPs) in chemoresistance of advanced prostate cancers has been established, we tested the effect of CT on phospho-Akt and survivin levels in PC-3M cells. Finally, the cytoprotective effect of CT on PC-3M cells was tested in the presence of PI3K inhibitors such as LY 294002 and wortmannin. Acutely added CT significantly attenuated apoptosis of PC cell lines in response to etoposide, dexamethasone and selenite treatment, but could not reduce paclitaxel-induced apoptosis. CT potently stimulated phospho-Akt and survivin synthesis in PC-3M cells in a sustained manner, and LY 294002 attenuated CT-induced survivin synthesis as well as apoptosis resistance. These results suggest that CT induces chemoresistance to etoposide, dexamethasone and selenite but not to paclitaxel in prostate cells. Cytoprotective action of CT is mediated by CTR-induced activation of Akt-survivin pathway. Since CT/CTR expression in prostate cancers increases with tumor progression, the suppression of "CT System" may enhance the effectiveness of chemotherapy.
Thomas
Shibu
S
University of Louisiana School of Pharmacy, College of Health Sciences, Monroe, Louisiana 71209, USA.
Shah
Girish
G
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002116:Calcitonin / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000187:drug effects; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002867:Chromones; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018003:Receptors, Calcitonin; D000077022:Survivin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002116:Calcitonin; D051057:Proto-Oncogene Proteins c-akt