Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2021; 12:2320-2320.

P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis

Jun Zhang _, Ke Ma, Tingting Qi, Xiaoning Wei, Qing Zhang, Guanwu Li and Jen-Fu Chiu

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Oncotarget. 2015; 6:789-801. https://doi.org/10.18632/oncotarget.2733

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Abstract

Jun Zhang1, Ke Ma1, Tingting Qi1, Xiaoning Wei1, Qing Zhang1, Guanwu Li1, Jen-Fu Chiu1

1Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China

Correspondence to:

Jen-Fu Chiu, e-mail: jfchiu@hku.hk

Guanwu Li, e-mail: gwli@stu.edu.cn

Keywords: apoptosis, autophagy, cell death, resveratrol, Fas/Cav-1 complex, P62

Received: August 27, 2014     Accepted: November 08, 2014     Published: November 29, 2014

ABSTRACT

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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