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Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway
Autophagy ( IF 14.6 ) Pub Date : 2019-11-27
Komal Qureshi-Baig, Diana Kuhn, Elodie Viry, Vitaly I. Pozdeev, Martine Schmitz, Fabien Rodriguez, Pit Ullmann, Eric Koncina, Martin Nurmik, Sonia Frasquilho, Petr V. Nazarov, Nikolaus Zuegel, Marc Boulmont, Yervand Karapetyan, Laurent Antunes, Daniel Val, Michel Mittelbronn, Bassam Janji, Serge Haan, Elisabeth Letellier

ABSTRACT

In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCα as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients.

Abbreviations: ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CQ: chloroquine; CSC: cancer stem cells; CRC: colorectal cancer; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PRKC/PKC: protein kinase C; SQSTM1/p62: sequestosome 1; TICs: tumor-initiating cells.



中文翻译:

缺氧诱导的自噬通过激活PRKC / PKC-EZR(ezrin)途径驱动大肠癌的发生和发展

抽象的

在实体瘤中,常在低氧环境中发现癌干细胞(CSC)或肿瘤起始细胞(TIC)。然而,低氧对TIC的影响知之甚少。使用先前建立的,TIC丰富的患者来源的结直肠癌(CRC)文化,我们显示低氧增加了TICs的自我更新能力,同时诱导了分化程度更高的对应文化中的增殖停滞。基因表达数据显示自噬/自噬是TICs低氧诱导的主要途径之一。有趣的是,发现缺氧诱导的自噬可诱导Thr567残基上的EZR(ezrin)磷酸化,可通过敲低ATG5,BNIP3,BNIP3LBECN1来逆转。此外,我们确定PRKCA /PKCα是参与缺氧诱导的自噬介导的TIC自我更新的潜在激酶。PRKC / PKC和EZR的自噬或药理学抑制的遗传靶向导致TICs的肿瘤启动潜力降低。此外,我们观察到稳定的ATG5敲除后体内肿瘤的发生和生长显着减少。对人类CRC样本的分析表明,位于肿瘤缺氧和自噬区域的TIC中通常存在p-EZR。总之,我们的结果将缺氧自噬-PKC-EZR信号轴确立为TIC自我更新和CRC进展的新型调节机制。因此,自噬抑制可能代表癌症患者有希望的治疗策略。

缩写:ATG:自噬相关;BECN1:beclin 1;BNIP3:BCL2相互作用蛋白3;BNIP3L:BCL2相互作用蛋白3样;CQ:氯喹;CSC:癌症干细胞;CRC:大肠癌;HIF1A /HIF-1α:缺氧诱导因子1亚基α;MAP1LC3 / LC3:微管相关蛋白1轻链3;PRKC / PKC:蛋白激酶C;SQSTM1 / p62:螯合体1;TIC:肿瘤引发细胞。

更新日期:2019-11-28
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