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αvβ3 INTEGRIN MEDIATES RADIORESISTANCE OF PROSTATE CANCER CELLS THROUGH REGULATION OF SURVIVIN.

The αvβ3 integrin is involved in various physiological and pathological processes such as wound healing, angiogenesis, tumor growth and metastasis. The impact of αvβ3 integrin on the radiosensitivity of prostate cancer (PrCa) cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with αvβ3 integrin and PC3 cells that contain endogenous β3 integrin were used. This study demonstrated that αvβ3 integrin increases survival of αvβ3-LNCaP cells upon IR while shRNA-mediated knockdown of αvβ3 integrin in PC-3 cells sensitizes to radiation. Expression of vβ3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αvβ3 integrin in PC3 cells inhibits anchorage-independent cell growth. The αvβ3 antagonist, cRGD, significantly increases radiosensitivity in both αvβ3-LNCaP and PC3 cells. Moreover, αvβ3 integrin prevents radiation-induced down-regulation 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 PC3 cells treated with αvβ3 integrin shRNA increases survival of cells upon IR. These findings reveal that αvβ3 integrin promotes radioresistance and regulates survivin levels in response to IR.

IMPLICATIONS: Future translational research on targeting αvβ3 integrin and survivin may reveal novel approaches as an adjunct to radiation therapy for PrCa patients.

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