Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma.
We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Wenjun
W
Zeng
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Chunyun
C
Zhang
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Hongwei
H
Cheng
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Yun-Long
YL
Wu
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Jie
J
Liu
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Zekun
Z
Chen
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Jian-Gang
JG
Huang
Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Singapore.
Russell Erick
RE
Ericksen
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Liqun
L
Chen
Department of Pathology, The First Hospital of Xiamen, Xiamen, China.
Haiping
H
Zhang
School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong, China. awong1@hku.hk.
Alice Sze Tsai
AS
Wong
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
Xiao-Kun
XK
Zhang
Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Singapore.
Weiping
W
Han
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. jzzeng@xmu.edu.cn.
Jin-Zhang
JZ
Zeng
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D047309:Flavones / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009857:Oncogenes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D016588:Anticarcinogenic Agents; D047309:Flavones; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid; D051028:bcl-2-Associated X Protein; D000097768:Retinoic Acid Receptor gamma; C494826:BAX protein, human; C023717:acacetin