P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis.
P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis.
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P62 调节白藜芦醇介导的 Fas/Cav-1 复合物形成以及从自噬到凋亡的转变。
DOI：
10.18632/oncotarget.2733
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发表时间：
2015-01-20
期刊：
影响因子：
--
通讯作者：
Chiu JF
中科院分区：
文献类型：
--
作者：
Zhang J;Ma K;Qi T;Wei X;Zhang Q;Li G;Chiu JF
白藜芦醇是一种潜在的用于癌症治疗的多酚药物。我们研究了RSV处理的非小肺腺癌A549细胞自噬和凋亡之间的关系。白藜芦醇处理增加了自噬和自噬介导的p62的降解。免疫细胞化学显示p62与Fas/Cav-1复合体共定位，可诱导细胞凋亡。然而，siRNA介导的p62下调促进了Fas/Cav-1复合体的形成，表明p62抑制了Fas/Cav-1复合体的形成。Fas/Cav-1复合体激活caspase-8，裂解Beclin-1，释放C端Beclin-1多肽，转位到线粒体，启动细胞凋亡。通过siRNA介导的Beclin-1抑制自噬也可阻断RSV诱导的细胞凋亡，表明细胞的凋亡依赖于自噬。P62基因被siRNA敲除可加速caspase-8的激活并启动细胞凋亡，而Cav-1基因敲除可抑制细胞的凋亡，但增加自噬。3-MA抑制自噬可阻止p62降解和诱导细胞凋亡，而z-IETD-FMK或z-DEVD-FMK抑制细胞凋亡可促进p62诱导和自噬细胞死亡。总而言之，p62将白藜芦醇诱导的自噬与细胞凋亡联系起来。P62通过抑制Fas/Cav-1复合体的形成来阻止细胞凋亡，但RSV诱导的P62自噬降解使Fas/Cav-1复合体的形成，然后激活caspase-8介导的Beclin-1裂解，导致Beclin-1C末端片段移位到线粒体，启动细胞凋亡。
Resveratrol is a potential polyphenol drug used in cancer treatment. We examined the relationship between autophagy and apoptosis in RSV-treated non-small lung adenocarcinoma A549 cells. Resveratrol treatment increased autophagy and autophagy-mediated degradation of P62. Immunocytochemistry revealed P62 co-localized with Fas/Cav-1 complexes, known to induce apoptosis. However, siRNA-mediated P62 downregulation enhanced formation of Fas/Cav-1 complexes, suggesting that P62 inhibited Fas/Cav-1 complex formation. Fas/Cav-1 complexes triggered caspase-8 activation and cleavage of Beclin-1, releasing a C-terminal Beclin-1 peptide that translocated to the mitochondria and initiate apoptosis. Inhibition of autophagy by siRNA-mediated repression of Beclin-1 also blocked RSV-induced apoptosis, showing a dependence of apoptosis on autophagy. P62 knockdown by siRNA accelerated the activation of caspase-8 and initiate apoptosis, while Cav-1 knockdown inhibited apoptosis, but increased autophagy. Inhibition of autophagy by 3-MA prevented both P62 degradation and induction of apoptosis, whereas inhibition of apoptosis by z-IETD-FMK or z-DEVD-FMK enhanced both P62 induction and autophagic cell death. In conclusion, P62 links resveratrol-induced autophagy to apoptosis. P62 blocks apoptosis by inhibiting Fas/Cav-1 complex formation, but RSV-induced autophagic degradation of P62 enables formation of Fas/Cav-1 complexes which then activate caspase-8-mediated Beclin-1 cleavage, resulting in translocation of the Beclin-1 C-terminal fragment to the mitochondria to initiate apoptosis.
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DOI：
10.18632/aging.100542
发表时间：
2013-03
期刊：
Aging
影响因子：
--
作者：
Lakshminarasimhan M;Rauh D;Schutkowski M;Steegborn C
通讯作者：
Steegborn C
影响因子：
13.3
作者：
Saiki, Shinji;Sasazawa, Yukiko;Hattori, Nobutaka
通讯作者：
Hattori, Nobutaka
影响因子：
13.3
作者：
Jaakkola, Panu M.;Pursiheimo, Juha-Pekka
通讯作者：
Pursiheimo, Juha-Pekka
影响因子：
64.5
作者：
ROTHBERG, KG;HEUSER, JE;ANDERSON, RGW
通讯作者：
ANDERSON, RGW
影响因子：
4.8
作者：
Han, Jie;Goldstein, Leslie A.;Rabinowich, Hannah
通讯作者：
Rabinowich, Hannah