Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, Massachusetts.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
Mol Cancer Res. 2019 Feb;17(2):398-408. doi: 10.1158/1541-7786.MCR-18-0544. Epub 2018 Sep 28.
The αβ integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of αβ 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 αβ integrin and PC-3 cells that contain endogenous β integrin were used. This study demonstrated that αβ integrin increases survival of αβ-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of αβ integrin in PC-3 cells sensitizes to radiation. Expression of αβ integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of αβ integrin in PC-3 cells inhibits anchorage-independent cell growth. The αβ antagonist, cRGD, significantly increases radiosensitivity in both αβ-LNCaP and PC-3 cells. Moreover, αβ 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 αβ integrin shRNA increases survival of cells upon IR. These findings reveal that αβ integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting αβ integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.
αβ 整合素参与多种生理和病理过程，如伤口愈合、血管生成、肿瘤生长和转移。本研究旨在探讨 αβ 整合素对前列腺癌细胞放射敏感性的影响及其控制细胞对电离辐射（IR）存活的分子机制。使用稳定转染 αβ 整合素的 LNCaP 细胞和含有内源性 β 整合素的 PC-3 细胞。本研究表明，αβ 整合素增加了 αβ-LNCaP 细胞在 IR 下的存活，而 shRNA 介导的 PC-3 细胞中 αβ 整合素的敲低使细胞对辐射敏感。LNCaP 细胞中 αβ 整合素的表达也增强了锚定非依赖性细胞生长，而 PC-3 细胞中 αβ 整合素的敲低抑制了锚定非依赖性细胞生长。αβ 拮抗剂 cRGD 显著增加了 αβ-LNCaP 和 PC-3 细胞的放射敏感性。此外，αβ 整合素可防止辐射诱导的 survivin 下调。siRNA 或 shRNA 抑制 survivin 的表达增强了 IR 诱导的锚定非依赖性细胞生长抑制。在接受 αβ 整合素 shRNA 处理的 PC-3 细胞中过表达野生型 survivin 可增加细胞在 IR 下的存活。这些发现表明，αβ 整合素促进放射抗性并调节 survivin 水平以响应 IR。意义：靶向 αβ 整合素和 survivin 的未来转化研究可能会揭示出针对前列腺癌患者放射治疗的新方法。
