Resveratrol-mediated downregulation of Rictor attenuates autophagic process and suppresses UV-induced skin carcinogenesis.
Resveratrol-mediated downregulation of Rictor attenuates autophagic process and suppresses UV-induced skin carcinogenesis.
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DOI：
10.1111/j.1751-1097.2012.01097.x
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发表时间：
2012-09
影响因子：
3.3
通讯作者：
Kim AL
中科院分区：
文献类型：
--
作者：
Back JH;Zhu Y;Calabro A;Queenan C;Kim AS;Arbesman J;Kim AL
大自噬是细胞对各种环境应激的反应，其确保溶酶体降解长寿命和受损的蛋白质和细胞器。它通过自噬体的形成而发生，然后自噬体与溶酶体融合形成自溶酶体。根据细胞环境，自噬可以促进癌细胞存活，或者它可以作为肿瘤抑制的机制。在此，我们表明，白藜芦醇，一种天然的植物抗毒素，诱导人A431 SCC细胞的早衰，白藜芦醇诱导的早衰与自溶体形成的封锁，如评估的情况下，共定位的LC 3和灯-2，标记自噬体和溶酶体，分别。此外，我们发现白藜芦醇下调mTORC 2的一个组成部分Rictor的水平，导致RhoA-GTbR减少和肌动蛋白细胞骨架组织改变。外源性Rictor过表达可恢复RhoA-GT3活性和肌动蛋白细胞骨架网络，并降低白藜芦醇诱导的衰老相关β-gal活性，表明Rictor在衰老诱导中的直接作用。Rictor在紫外线诱导的小鼠SCC中过表达，而口服白藜芦醇可降低其表达。这些数据表明，白藜芦醇通过Rictor减弱自噬过程，并表明Rictor的下调可能是与早衰相关的肿瘤抑制机制。
Macroautophagy is a cellular response to various environmental stresses that ensures lysosomal degradation of long-lived and damaged proteins and cellular organelles. It occurs through the formation of an autophagosome, which then fuses with a lysosome to form an autolysosome. Depending on the cellular context, autophagy may promote cancer cell survival or it may serve as a mechanism of tumor suppression. Herein, we show that resveratrol, a natural phytoalexin, induces premature senescence in human A431 SCC cells, and that resveratrol-induced premature senescence is associated with a blockade of autolysosome formation, as assessed by the absence of colocalization of LC3 and Lamp-2, markers for autophagosomes and lysosomes, respectively. Further, we show that resveratrol downregulates the level of Rictor, a component of mTORC2, leading to decreased RhoA-GTPase and altered actin cytoskeleton organization. Exogenous overexpression of Rictor restores RhoA-GTPase activity and actin cytoskeleton network, and decreases resveratrol-induced senescence-associated β-gal activity, indicating a direct role of Rictor in senescence induction. Rictor is overexpressed in UV-induced murine SCCs, whereas its expression is diminished by oral administration of resveratrol. These data indicate that resveratrol attenuates autophagic process via Rictor, and suggest that downregulation of Rictor may be a mechanism of tumor suppression associated with premature senescence.
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影响因子：
10.6
作者：
Kaushik, S.;Cuervo, A. M.
通讯作者：
Cuervo, A. M.
影响因子：
3.9
作者：
Gerland, LM;Peyrol, S;Ffrench, M
通讯作者：
Ffrench, M
影响因子：
10.3
作者：
Feldmeyer, L.;Hofbauer, G. F. L.;Hafner, J.
通讯作者：
Hafner, J.
影响因子：
6.5
作者：
Kim, AL;Athar, M;Gautier, J
通讯作者：
Gautier, J
DOI：
10.18632/aging.100056
发表时间：
2009-06-03
期刊：
Aging
影响因子：
--
作者：
Armour SM;Baur JA;Hsieh SN;Land-Bracha A;Thomas SM;Sinclair DA
通讯作者：
Sinclair DA