Ren Yan, Yeoh Kheng Wei, Hao Piliang, Kon Oi Lian, Sze Siu Kwan
School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.
BGI-Shenzhen , Yantian District Beishan Industrial Zone 11th building, Shenzhen, China 518083.
J Proteome Res. 2016 Dec 2;15(12):4258-4264. doi: 10.1021/acs.jproteome.6b00340. Epub 2016 Nov 10.
Hypoxia is thought to promote tumor radio-resistance via effects on gene expression in cancer cells that modulate their metabolism, proliferation, and DNA repair pathways to enhance survival. Here we demonstrate for the first time that under hypoxic condition A431 epithelial carcinoma cells exhibit increased viability when exposed to low-dose γ-irradiation, indicating that radiotherapy can promote tumor cell survival when oxygen supply is limited. When assessed using iTRAQ quantitative proteomics and Western blotting, irradiated tumor cells were observed to significantly up-regulate the expression of calcium-binding proteins CALM1, CALU, and RCN1, suggesting important roles for these mediators in promoting tumor cell survival during hypoxia. Accordingly, shRNA-knockdown of CALM1, CALU, and RCN1 expression reduced hypoxic tumor cell resistance to low-dose radiation and increased apoptosis. These data indicate that γ-irradiation of hypoxic tumor cells induces up-regulation of calcium-binding proteins that promote cancer cell survival and may limit the efficacy of radiotherapy in the clinic.
缺氧被认为通过影响癌细胞中的基因表达来促进肿瘤放射抗性，这些基因表达调节癌细胞的代谢、增殖和DNA修复途径以提高存活率。在此，我们首次证明，在缺氧条件下，A431上皮癌细胞在暴露于低剂量γ射线照射时表现出活力增加，这表明当氧气供应有限时，放疗可促进肿瘤细胞存活。当使用iTRAQ定量蛋白质组学和蛋白质印迹法进行评估时，观察到受照射的肿瘤细胞显著上调钙结合蛋白CALM1、CALU和RCN1的表达，表明这些介质在缺氧期间促进肿瘤细胞存活中起重要作用。因此，shRNA敲低CALM1、CALU和RCN1的表达降低了缺氧肿瘤细胞对低剂量辐射的抗性并增加了细胞凋亡。这些数据表明，缺氧肿瘤细胞的γ射线照射诱导促进癌细胞存活的钙结合蛋白上调，并可能限制临床放疗的疗效。
