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

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

SUBMITTER: Wang T

PROVIDER: S-EPMC6359981 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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αvβ3 Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin.

Wang Tao T Huang Jiayi J Vue Mai M Alavian Michael R MR Goel Hira Lal HL Altieri Dario C DC Languino Lucia R LR FitzGerald Thomas J TJ

Molecular cancer research : MCR 20180928 2

The αvβ3 integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of αvβ3 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 αvβ3 integrin and PC-3 cells that contain endogenous β3 ...[more]

PMID: 30266752

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Project description:BackgroundProstate cancer is a leading cause of cancer-related death in men worldwide. Survivin is a member of the inhibitor of apoptosis (IAP) protein family that is expressed in the majority of human tumors including prostate cancer, but is barely detectable in terminally differentiated normal cells. Downregulation of survivin could sensitize prostate cancer cells to chemotherapeutic agents in vitro and in vivo. Selenium is an essential trace element. Several studies have shown that selenium compounds inhibit the growth of prostate cancer cells. The objective of this study is to investigate whether survivin gene silencing in conjunction with selenium treatment could enhance the therapeutic efficacy for prostate cancer and to elucidate the underlying mechanisms.MethodsExpression of survivin was analyzed in a collection of normal and malignant prostatic tissues by immunohistochemical staining. In vitro studies were conducted in PC-3M, C4-2B, and 22Rv1 prostate cancer cells. The effect of selenium on survivin expression was analyzed by Western blotting and semi-quantitative RT-PCR. Survivin gene knockdown was carried out by transfecting cells with a short hairpin RNA (shRNA) designed against survivin. Cell proliferation was quantitated by the 3-(4,5-Dimethylthiazol-2-yl)- 2,5-Diphenyltetrazolium Bromide (MTT) assay and apoptosis by propidium iodide staining followed by flow cytometry analysis. Finally, in vivo tumor growth assay was performed by establishing PC-3M xenograft in nude mice and monitoring tumor growth following transfection and treatment.ResultsWe found that survivin was undetectable in normal prostatic tissues but was highly expressed in prostate cancers. Survivin knockdown or selenium treatment inhibited the growth of prostate cancer cells, but the selenium effect was modest. In contrast to what have been observed in other cell lines, selenium treatment had little or no effect on survivin expression in several androgen-independent prostate cancer cell lines. Survivin knockdown sensitized these cells to selenium growth inhibition and apoptosis induction. In nude mice bearing PC-3M xenografts, survivin knockdown synergizes with selenium in inhibiting tumor growth.ConclusionsSelenium could inhibit the growth of hormone-refractory prostate cancer cells both in vitro and in vivo, but the effects were modest. The growth inhibition was not mediated by downregulating survivin expression. Survivin silencing greatly enhanced the growth inhibitory effects of selenium.

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

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α<sub>v</sub>β<sub>3</sub> Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin.

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