ABSTRACT
The αvß3 integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of αvß3 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 αvß3 integrin and PC-3 cells that contain endogenous ß3 integrin were used. This study demonstrated that αvß3 integrin increases survival of αvß3-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of αvß3 integrin in PC-3 cells sensitizes to radiation. Expression of αvß3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αvß3 integrin in PC-3 cells inhibits anchorage-independent cell growth. The αvß3 antagonist, cRGD, significantly increases radiosensitivity in both αvß3-LNCaP and PC-3 cells. Moreover, αvß3 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 αvß3 integrin shRNA increases survival of cells upon IR. These findings reveal that αvß3 integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting αvß3 integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.
Subject(s)
Integrin alphaVbeta3/metabolism , Prostatic Neoplasms/genetics , Survivin/metabolism , Cell Line, Tumor , Cell Survival/physiology , Cell Survival/radiation effects , Down-Regulation/radiation effects , Humans , Integrin alphaVbeta3/biosynthesis , Integrin alphaVbeta3/genetics , Male , Oligopeptides/pharmacology , PC-3 Cells , Prostatic Neoplasms/pathology , Prostatic Neoplasms/radiotherapy , RNA Interference , Radiation Tolerance , Survivin/biosynthesis , Survivin/genetics , TransfectionABSTRACT
BACKGROUND: Cell adhesion plays an important role in proliferation, metastasis, and tumor growth and may represent a potential vulnerability in treatment of prostate cancer patients. Bicalutamide (Casodex) has been used as an anti-androgen agent for prostate cancer patients during hormone ablation therapy. This study focuses on the effect of Bicalutamide on cell adhesion to fibronectin (FN) in prostate cancer cells. METHODS: Androgen-dependent LNCaP prostate cancer cells were stimulated with androgen before being irradiated with doses of 0, 5, 10, or 15 Gy. Cell adhesion to fibronectin was then measured to ascertain androgen's role in integrin mediated prostate cancer cell adhesion. Flow cytometry was used to analyze surface expression of integrin subtypes in LNCaP cells. RESULTS: LNCaP cell adhesion to FN was significantly increased by stimulation with androgen when treated with 10 or 15 Gy ionizing radiations but not at 0 or 5 Gy. This increase was inhibited by treatment with Bicalutamide. LNCaP cells exposed to high dose radiation showed an increased expression of alpha(V) and beta(1) integrins in response to androgen treatment while Bicalutamide abolished this effect. CONCLUSIONS: Our data show that Bicalutamide inhibits the effect of androgen on cell adhesion to FN through changes of integrin subtypes in cells given high dose radiation. This suggests new molecular targets and possible treatment strategies for prostate cancer patients to improve the outcome during hormone ablation therapy and radiation therapy.
