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.