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


METHODS
The effects of TNF-α 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.


RESULTS
TNF-α rapidly and potently induced the expression of Nur77 in breast cancer cells through activation of IκB kinase and JNK. Knocking down Nur77 resulted in TNF-α-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-α-induced apoptosis by inhibiting TNF-α-induced Nur77 mRNA expression, which could be attributed to its interference of TNFR1's interaction with receptor-interacting protein 1 (RIPK1).


CONCLUSIONS
TNF-α-induced Nur77 serves as a survival factor to attenuate the death effect of TNF-α in cancer cells. With its proven human safety profile, honokiol represents a promising agent that warrants further clinical development.
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Lei
L
Xie
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Fuquan
F
Jiang
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Xindao
X
Zhang
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Gulimiran
G
Alitongbieke
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Xinlei
X
Shi
Zhongshan Hospital, Xiamen University, Xiamen, 361102, China.
MinJun
M
Meng
Zhongshan Hospital, Xiamen University, Xiamen, 361102, China.
Yiming
Y
Xu
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Anshi
A
Ren
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Jing
J
Wang
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Lijun
L
Cai
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Yunxia
Y
Zhou
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Yang
Y
Xu
Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, CA, 92037, USA.
Ying
Y
Su
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Jie
J
Liu
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Zhiping
Z
Zeng
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Guanghui
G
Wang
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Hu
H
Zhou
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
Quan Cheng
QC
Chen
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.|Sanford Burnham Prebys Medical Discovery Institute Cancer Center, La Jolla, CA, 92037, USA.
Xiao-Kun
XK
Zhang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D004365:Drugs, Chinese Herbal; D017705:Lignans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014409:Tumor Necrosis Factor-alpha; C539821:NR4A1 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols