α_vβ₃ Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin

The α_vβ₃ integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of α_vβ₃ 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 α_vβ₃ integrin and PC-3 cells that contain endogenous β₃ integrin were used. This study demonstrated that α_vβ₃ integrin increases survival of α_vβ₃-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of α_vβ₃ integrin in PC-3 cells sensitizes to radiation. Expression of α_vβ₃ integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of α_vβ₃ integrin in PC-3 cells inhibits anchorage-independent cell growth. The α_vβ₃ antagonist, cRGD, significantly increases radiosensitivity in both α_vβ₃-LNCaP and PC-3 cells. Moreover, α_vβ₃ 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 α_vβ₃ integrin shRNA increases survival of cells upon IR. These findings reveal that α_vβ₃ integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting α_vβ₃ integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.