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

Mol Cancer Res. 2019 Feb;17(2):398-408. doi: 10.1158/1541-7786.MCR-18-0544. Epub 2018 Sep 28.

Abstract

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 integrin were used. This study demonstrated that αvβ3 integrin increases survival of αvβ3-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of αvβ3 integrin in PC-3 cells sensitizes to radiation. Expression of αvβ3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αvβ3 integrin in PC-3 cells inhibits anchorage-independent cell growth. The αvβ3 antagonist, cRGD, significantly increases radiosensitivity in both αvβ3-LNCaP and PC-3 cells. Moreover, αvβ3 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 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 radiotherapy for patients with prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / physiology
  • Cell Survival / radiation effects
  • Down-Regulation / radiation effects
  • Humans
  • Integrin alphaVbeta3 / biosynthesis
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism*
  • Male
  • Oligopeptides / pharmacology
  • PC-3 Cells
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / radiotherapy
  • RNA Interference
  • Radiation Tolerance
  • Survivin / biosynthesis
  • Survivin / genetics
  • Survivin / metabolism*
  • Transfection

Substances

  • BIRC5 protein, human
  • Integrin alphaVbeta3
  • Oligopeptides
  • Survivin
  • arginyl-glycyl-aspartic acid