Taguchi Yuki, Horiuchi Yuta, Kano Fumi, Murata Masayuki
Laboratory of Frontier Image Analysis, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Cell Death Dis. 2017 Mar 30;8(3):e2718. doi: 10.1038/cddis.2017.147.
Cancer cells are under chronic endoplasmic reticulum (ER) stress due to hypoxia, low levels of nutrients, and a high metabolic demand for proliferation. To survive, they constitutively activate the unfolded protein response (UPR). The inositol-requiring protein 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) signaling branches of the UPR have been shown to have cytoprotective roles in cancer cells. UPR-induced autophagy is another prosurvival strategy of cancer cells, possibly to remove misfolded proteins and supply nutrients. However, the mechanisms by which cancer cells exploit the UPR and autophagy machinery to promote survival and the molecules that are essential for these processes remain to be elucidated. Recently, a multipass membrane protein, Yip1A, was shown to function in the activation of IRE1 and in UPR-induced autophagy. In the present study, we explored the possible role of Yip1A in activation of the UPR by cancer cells for their survival, and found that depletion of Yip1A by RNA interference (RNAi) induced apoptotic cell death in HeLa and CaSki cervical cancer cells. Intriguingly, Yip1A was found to activate the IRE1 and PERK pathways of the UPR constitutively in HeLa and CaSki cells. Yip1A mediated the phosphorylation of IRE1 and also engaged in the transcription of PERK. The activation of these signaling pathways upregulated the expression of anti-apoptotic proteins and autophagy-related proteins. These events might enhance resistance to apoptosis and promote cytoprotective autophagy in HeLa and CaSki cells. The present study is the first to uncover a key prosurvival modulator, Yip1A, which coordinates IRE1 signaling with PERK signaling to support the survival of HeLa and CaSki cervical cancer cells.
由于缺氧、营养物质水平低以及增殖对代谢的高需求，癌细胞处于慢性内质网（ER）应激状态。为了存活，它们持续激活未折叠蛋白反应（UPR）。UPR的肌醇需求蛋白1（IRE1）和蛋白激酶RNA样内质网激酶（PERK）信号分支已被证明在癌细胞中具有细胞保护作用。UPR诱导的自噬是癌细胞的另一种促生存策略，可能用于清除错误折叠的蛋白质并提供营养物质。然而，癌细胞利用UPR和自噬机制促进存活的机制以及这些过程所必需的分子仍有待阐明。最近，一种多次跨膜蛋白Yip1A被证明在IRE1的激活和UPR诱导的自噬中发挥作用。在本研究中，我们探讨了Yip1A在癌细胞激活UPR以促进其存活中的可能作用，发现通过RNA干扰（RNAi）耗尽Yip1A会诱导HeLa和CaSki宫颈癌细胞发生凋亡性细胞死亡。有趣的是，在HeLa和CaSki细胞中发现Yip1A持续激活UPR的IRE1和PERK途径。Yip1A介导IRE1的磷酸化，还参与PERK的转录。这些信号通路的激活上调了抗凋亡蛋白和自噬相关蛋白的表达。这些事件可能增强HeLa和CaSki细胞对凋亡的抗性并促进细胞保护性自噬。本研究首次揭示了一种关键的促生存调节因子Yip1A，它协调IRE1信号与PERK信号以支持HeLa和CaSki宫颈癌细胞的存活。
