Poly C binding protein 1 represses autophagy through downregulation of LC3B to promote tumor cell apoptosis in starvation
Poly C binding protein 1 represses autophagy through downregulation of LC3B to promote tumor cell apoptosis in starvation
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DOI：
10.1016/j.biocel.2016.02.009
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发表时间：
2016-04-01
影响因子：
4
通讯作者：
Wang, Haihe
中科院分区：
文献类型：
--
作者：
Zhang, Wenliang;Shi, Hongshun;Wang, Haihe
越来越多的证据表明，多聚C结合蛋白1（polyC binding protein，PCBP 1）作为一种抑癌基因在多种肿瘤中表达下调，但其抑制肿瘤发生的机制尚不清楚。在这里，我们发现PCBP 1过表达在无血清饥饿时减弱肿瘤细胞生长。值得注意的是，自噬降解抑制剂氯喹可以模拟肿瘤细胞生长中的这种抑制作用。自噬分析表明，PCBP 1过表达阻断了饥饿条件下肿瘤细胞的自噬通量，而PCBP 1下调反过来又补充了这种自噬通量，保护细胞免于死亡。机制上，PCBP 1过表达减弱微管相关蛋白轻链3（LOB）mRNA的稳定性，抑制LC 3B的表达，导致自噬抑制。因此，PCBP 1过表达强烈地触发了caspase 3和8介导的肿瘤细胞凋亡，并在饥饿时下调了抗凋亡BcI-2的表达，这可以被自噬抑制剂进一步协同，表明PCBP 1不仅抑制肿瘤细胞自噬，而且使其凋亡。总之，我们的研究结果揭示了PCBP 1抑制自噬介导的细胞存活的新机制，并表明通过PCBP 1上调或用自噬抑制剂抑制肿瘤细胞自噬可能是PCBP 1低表达的结肠和卵巢肿瘤的有效治疗策略。(C)2016爱思唯尔有限公司版权所有
Accumulating evidences indicate that poly C binding protein (PCBP1) is downregulated in various carcinomas as a tumor suppressor, but the underlying mechanism in suppression of tumorigenesis still remains elusive. Here, we found that PCBP1 overexpression attenuates tumor cell growth upon serum free starvation. Notably, the autophagic degradation inhibitor, chloroquine, could mimic this suppressive effect in tumor cell growth. Autophagy analyses demonstrated that PCBP1 overexpression blocked autophagic flux of tumor cells under starvation conditions, while PCBP1 downregulation in turn refueled this autophagic flux, protecting cells from death. Mechanistically, PCBP1 overexpression attenuated microtubule-associated protein Light chain 3 (LOB) mRNA stability to repress LC3B expression, resulting in the autophagy inhibition. Consequently, PCBP1 overexpression strongly triggered the caspase 3 and 8-mediated apoptosis of tumor cells and downregulated anti-apoptotic BcI-2 expression upon starvation, which could be further synergized by autophagic inhibitor, indicating that PCBP1 not only inhibits tumor cell autophagy, but also renders them to apoptosis. Taken together, our results uncovered a novel mechanism of PCBP1 in repressing autophagy-mediated cell survival and indicated that inhibition of tumor cell autophagy by PCBP1 upregulation or with autophagic inhibitors could be an effective therapeutical strategy to colon and ovary tumors with low PCBP1 expression. (C) 2016 Elsevier Ltd. All rights reserved.