The putative oncotarget CSN5 controls a transcription-uncorrelated p53-mediated autophagy implicated in cancer cell survival under curcumin treatment
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Qing-Yu Zhang1,2,*, Rui Jin2,*, Xian Zhang1,2,*, Ji-Po Sheng2, Fang Yu2, Ren-Xiang Tan1, Ying Pan1, Jun-Jian Huang2, Ling-Dong Kong1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
2Institute of Biotechnology, AMMS, Beijing 100850, P. R. China
*These authors contributed equally to this work
Ling-Dong Kong, email: firstname.lastname@example.org
Jun-Jian Huang, email: email@example.com
Keywords: curcumin, CSN5, p53, autophagy, cancer cell-killing effect
Received: April 21, 2016 Accepted: September 02, 2016 Published: September 10, 2016
Curcumin has shown promise as a safe and specific anticancer agent. The COP9 signalosome (CSN) component CSN5, a known specific target for curcumin, can control p53 stability by increasing its degradation through ubiquitin system. But the correlation of CSN5-controlled p53 to anticancer therapeutic effect of curcumin is currently unknown. Here we showed that CSN5-controlled p53 was transcriptional inactive and responsible for autophagy in human normal BJ cells and cancer HepG2 cells under curcumin treatment. Of note, CSN5-initiated cellular autophagy by curcumin treatment was abolished in p53-null HCT116p53−/− cancer cells, which could be rescued by reconstitution with wild-type p53 or transcription inactive p53 mutant p53R273H. Furthermore, CSN5-controlled p53 conferred a pro-survival autophagy in diverse cancer cells response to curcumin. Genetic p53 deletion, as well as autophagy pharmacological inhibition by chloroquine, significantly enhanced the therapeutic effect of curcumin on cancer cells in vitro and in vivo, but not normal cells. This study identifies a novel CSN5-controlled p53 in autophagy of human cells. The p53 expression state is a useful biomarker for predicting the anticancer therapeutic effect of curcumin. Therefore, the pharmacologic autophagy manipulation may benefit the ongoing anticancer clinical trials of curcumin.
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