Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells

• sAC plays an essential role in modulating proliferation and apoptosis.
• We examined the role of sAC in radioresistance of prostate cancer cells.
• sAC inhibition potentiated cytostatic and cytotoxic effects of irradiation.
• Overexpression of sAC in normal PNT2 cells reduced effects of irradiation.
• Downstream B-Raf/ERK1/2 signaling is responsible for sAC-dependent radioresistance.

Pharmacological modulation of tumor radiosensitivity is a promising strategy for enhancing the outcome of radiotherapy. cAMP signaling plays an essential role in modulating the proliferation and apoptosis of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In the present study, the role of an alternative source of cAMP, the intracellular localized soluble adenylyl cyclase (sAC), in the radiosensitivity of prostate cancer cells was investigated. Pharmacological inhibition of sAC activity led to marked suppression of proliferation, lactate dehydrogenase release, and induction of apoptosis. The combination of ionizing radiation with partial suppression of sAC activity (~ 50%) immediately after irradiation synergistically inhibited proliferation and induced apoptosis. Overexpression of sAC in normal prostate epithelial PNT2 cells increased the cAMP content and accelerated cell proliferation under control conditions. The effects of radiation were significantly reduced in transformed PNT2 cells compared with control cells. Analysis of the underlying cellular mechanisms of sAC-induced radioresistance revealed the sAC-dependent activation of B-Raf/ERK1/2 signaling. In agreement with this finding, inhibition of ERK1/2 in prostate cancer cells enhanced the cytotoxic effect of irradiation. In conclusion, the present study suggests that sAC-dependent signaling plays an important role in the radioresistance of prostate cancer cells. This article is part of a Special Issue entitled: The role of soluble adenylyl cyclase in health and disease.