Cell Death Triggered by the Autophagy Inhibitory Drug 3-Methyladenine in Growing Conditions Proceeds With DNA Damage.
Cell Death Triggered by the Autophagy Inhibitory Drug 3-Methyladenine in Growing Conditions Proceeds With DNA Damage.
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DOI：
10.3389/fphar.2020.580343
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发表时间：
2020
影响因子：
5.6
通讯作者：
Ribas J
中科院分区：
文献类型：
--
作者：
Chicote J;Yuste VJ;Boix J;Ribas J
巨噬（以下简称自噬）是一个多步骤的细胞内分解代谢过程，对细胞命运具有多效性影响。根据自噬的激活情况，自噬可分为诱导型和组成型。本构性或基础自噬在营养充足的条件下展开，以维持细胞的稳态。自噬抑制药物是探究自噬作用及其对细胞命运影响的有力工具。然而，3-甲基腺嘌呤和这些化合物中的许多都具有触发细胞死亡的内在能力，例如广泛使用的3-甲基腺嘌呤。为了阐明抑制基础自噬是否导致细胞死亡，我们使用了几种在自噬过程的不同阶段起作用的代表性化合物：起始（SBI0206965和MHY1485），成核（3-甲基腺嘌呤，SAR405， Spautin-1和Cpd18）和完成（巴菲霉素A1和氯喹）。这些化合物在生长条件下抑制MEF培养物的基础自噬。其中，3-甲基腺嘌呤、SBI-0206965、氯喹和Bafilomycin A1触发BAX和/或bac依赖性细胞毒性和caspase激活。3-甲基腺嘌呤是唯一的化合物，诱导细胞活力在一系列本体无关的人类细胞系一致和突然下降。3-甲基腺嘌呤诱导的细胞毒性不是由抑制AKT/mTOR轴驱动的。自噬缺陷的Fip200−/−mef对3-甲基腺嘌呤激活半胱天蛋白酶和细胞死亡的敏感性增加。γ-H2A.X显示，3-甲基腺嘌呤诱导的细胞毒性与大量DNA损伤相关。这种遗传毒性在10 mM 3-甲基腺嘌呤中观察到，这是抑制自噬的通常浓度，在Fip200−/−mef中达到最大。总之，我们的研究结果表明，在生长条件下，自噬可以作为一种保护机制来降低3-甲基腺嘌呤的内在细胞毒性。然而，当3-甲基腺嘌呤施加的细胞应激超过基础自噬的保护作用时，caspase激活和DNA损伤损害细胞活力。
Macroautophagy (hereafter autophagy) is a multistep intracellular catabolic process with pleiotropic implications in cell fate. Attending to its activation, autophagy can be classified into inducible or constitutive. Constitutive, or basal autophagy, unfolds under nutrient-replete conditions to maintain the cellular homeostasis. Autophagy inhibitory drugs are powerful tools to interrogate the role of autophagy and its consequences on cell fate. However, 3-methyladenine and various of these compounds present an intrinsic capacity to trigger cell death, for instance the broadly-employed 3-methyladenine. To elucidate whether the inhibition of basal autophagy is causative of cell demise, we have employed several representative compounds acting at different phases of the autophagic process: initiation (SBI0206965 and MHY1485), nucleation (3-methyladenine, SAR405, Spautin-1 and Cpd18), and completion (Bafilomycin A1 and Chloroquine). These compounds inhibited the basal autophagy of MEF cultures in growing conditions. Among them, 3-methyladenine, SBI-0206965, Chloroquine, and Bafilomycin A1 triggered BAX- and/or BAK-dependent cytotoxicity and caspase activation. 3-methyladenine was the only compound to induce a consistent and abrupt decrease in cell viability across a series of ontologically unrelated human cell lines. 3-methyladenine-induced cytotoxicity was not driven by the inhibition of the AKT/mTOR axis. Autophagy-deficient Fip200−/− MEFs displayed an increased sensitivity to activate caspases and to undergo cell death in response to 3-methyladenine. The cytotoxicity induced by 3-methyladenine correlated with a massive DNA damage, as shown by γ-H2A.X. This genotoxicity was observed at 10 mM 3-methyladenine, the usual concentration to inhibit autophagy and was maximized in Fip200−/− MEFs. In sum, our results suggest that, in growing conditions, autophagy acts as a protective mechanism to diminish the intrinsic cytotoxicity of 3-methyladenine. However, when the cellular stress exerted by 3-methyladenine surpasses the protective effect of basal autophagy, caspase activation and DNA damage compromise the cell viability.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
11.4
作者：
Brunn, GJ;Williams, J;Abraham, RT
通讯作者：
Abraham, RT
影响因子：
3.5
作者：
Iwashita H;Sakurai HT;Nagahora N;Ishiyama M;Shioji K;Sasamoto K;Okuma K;Shimizu S;Ueno Y
通讯作者：
Ueno Y
DOI：
10.1158/1541-7786.mcr-11-0098
发表时间：
2011-09
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Bae H;Guan JL
通讯作者：
Guan JL
影响因子：
13.3
作者：
Itakura, Eisuke;Mizushima, Noboru
通讯作者：
Mizushima, Noboru