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Honokiol sensitizes breast cancer cells to TNF-? induction of apoptosis by inhibiting Nur77 expression.

ABSTRACT:

Background and purpose

The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-? in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy.

Experimental approach

The effects of TNF-? on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expression was evaluated in tumour tissues from breast cancer patients. The anticancer effects of honokiol and its mechanism of action were assessed by in vitro, cell-based and animal studies.

Key results

TNF-? rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of I?B kinase and JNK. Knocking down Nur77 resulted in TNF-?-dependent apoptosis, while ectopic Nur77 expression in MCF-7 cells promoted their growth in animals. Levels of Nur77 were higher in tumour tissues than the corresponding tissues surrounding the tumour in about 50% breast cancer patients studied. Our in vitro and animal studies also identified honokiol as an effective sensitizer of TNF-?-induced apoptosis by inhibiting TNF-?-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1).

Conclusions and implications

TNF-?-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-? in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.

SUBMITTER: Xie L

PROVIDER: S-EPMC4940620 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

Honokiol sensitizes breast cancer cells to TNF-α induction of apoptosis by inhibiting Nur77 expression.

Xie Lei L Jiang Fuquan F Zhang Xindao X Alitongbieke Gulimiran G Shi Xinlei X Meng MinJun M Xu Yiming Y Ren Anshi A Wang Jing J Cai Lijun L Zhou Yunxia Y Xu Yang Y Su Ying Y Liu Jie J Zeng Zhiping Z Wang Guanghui G Zhou Hu H Chen Quan Cheng QC Zhang Xiao-Kun XK

British journal of pharmacology 20151216 2

<h4>Background and purpose</h4>The orphan nuclear receptor Nur77 is implicated in the survival and apoptosis of cancer cells. The purpose of this study was to determine whether and how Nur77 serves to mediate the effect of the inflammatory cytokine TNF-α in cancer cells and to identify and characterize new agents targeting Nur77 for cancer therapy.<h4>Experimental approach</h4>The effects of TNF-α on the expression and function of Nur77 were studied using in vitro and in vivo models. Nur77 expre ...[more]

PMID: 26505879

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Project description:Cancer cells hijack autophagy pathway to evade anti-cancer therapeutics. Many molecular signaling pathways associated with drug-resistance converge on autophagy induction. Honokiol (HNK), a natural phenolic compound purified from Magnolia grandiflora, has recently been shown to impede breast tumorigenesis and, in the present study, we investigated whether breast cancer cells evoke autophagy to modulate therapeutic efficacy and functional networks of HNK. Indeed, breast cancer cells exhibit increased autophagosomes-accumulation, MAP1LC3B-II/LC3B-II-conversion, expression of ATG proteins as well as elevated fusion of autophagosomes and lysosomes upon HNK treatment. Breast cancer cells treated with HNK demonstrate significant growth inhibition and apoptotic induction, and these biological processes are blunted by macroautophagy/autophagy. Consequently, inhibiting autophagosome formation, abrogating autophagosome-lysosome fusion or genetic-knockout of BECN1 and ATG7 effectively increase HNK-mediated apoptotic induction and growth inhibition. Next, we explored the functional impact of tumor suppressor STK11 in autophagy induction in HNK-treated cells. STK11-silencing abrogates LC3B-II-conversion, and blocks autophagosome/lysosome fusion and lysosomal activity as illustrated by LC3B-Rab7 co-staining and DQ-BSA assay. Our results exemplify the cytoprotective nature of autophagy invoked in HNK-treated breast cancer cells and put forth the notion that a combined strategy of autophagy inhibition with HNK would be more effective. Indeed, HNK and chloroquine (CQ) show synergistic inhibition of breast cancer cells and HNK-CQ combination treatment effectively inhibits breast tumorigenesis and metastatic progression. Tumor-dissociated cells from HNK-CQ treated tumors exhibit abrogated invasion and migration potential. Together, these results implicate that breast cancer cells undergo cytoprotective autophagy to circumvent HNK and a combined treatment with HNK and CQ can be a promising therapeutic strategy for breast cancer.