α v β 3 Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin.

The alpha(v)beta(3) integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of alpha(v)beta(3) integrin on the radiosensitivity of prostate cancer cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with alpha(v)beta(3) integrin and PC-3 cells that contain endogenous beta(3) integrin were used. This study demonstrated that alpha(v)beta(3) integrin increases survival of alpha(v)beta(3)-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of alpha(v)beta(3) integrin in PC-3 cells sensitizes to radiation. Expression of alpha(v)beta(3) integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of alpha(v)beta(3) integrin in PC-3 cells inhibits anchorage-independent cell growth. The alpha(v)beta(3) antagonist, cRGD, significantly increases radiosensitivity in both alpha(v)beta(3)-LNCaP and PC-3 cells. Moreover, alpha(v)beta(3) integrin prevents radiation-induced downregulation of survivin. Inhibition of survivin expression by siRNA or shRNA enhances IR-induced inhibition of anchorage-independent cell growth. Overexpression of wild-type survivin in PC-3 cells treated with alpha(v)beta(3) integrin shRNA increases survival of cells upon IR. These findings reveal that alpha(v)beta(3) integrin promotes radioresistance and regulates survivin levels in response to IR. Implications: Future translational research on targeting alpha(v)beta(3) integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.