Abstract
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.
Highlights
IntroductionCSN5 is a dominant component of the cytoplasmic COP9 signalosome (CSN) protein complex [1, 2]
Cancer is a leading cause of death around the world
We found that curcumin conferred a rapid downregulating effect on CSN5 protein expression at 6 h posttreatment in human hepatic carcinoma HepG2 cells in the dose-dependent manner, but CSN5 down-regulation was not observed for other anticancer drugs including etoposide, fluorouracil (5-FU) and cisplatin in the same cells even for long time exposure (18 h) (Figure 1A)
Summary
CSN5 is a dominant component of the cytoplasmic COP9 signalosome (CSN) protein complex [1, 2]. CSN5 is over-expressed in different human cancers [1, 3]. CSN5 can sequester p53 at the cytoplasm by either directly binding to promote the protein into the ubiquitin-proteasome-mediated protein degradation, or by linking the protein to the COP9 complex [7, 8]. Silencing CSN5 triggers cancer cell apoptosis with significant upregulation of p53 protein [7, 8]. P53 inhibition is a proposed role of CSN5 in cancers [1, 3]. Curcumin induces cancer cell apoptosis concomitantly with CSN5 down-regulation and p53 accumulation, underlying its anticancer activity [1, 8]
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