The anticancer effect of oridonin is mediated by fatty acid synthase suppression in human colorectal cancer cells.
BACKGROUND
Fatty acid synthase (FAS) inhibitors could be a therapeutic target in cancer treatment. However, only a few FAS inhibitors showing clinical potential have been reported. Oridonin is a diterpenoid isolated from Rabdosia rubescens. Although it has antiproliferative activity in cancers, little was known about its anticancer effect on colorectal cancer. In this regard, we aimed to investigate if oridonin could be a novel FAS inhibitor and its anticancer mechanism in human colorectal cancer cells.


METHODS
Two human colorectal cancer cell lines SW480 and SW620 were used as models for this study.


RESULTS
We demonstrated that oridonin reduced viability and induced apoptosis in colorectal cancer cells. Knockdown of the expression of FAS in colorectal cancer cells by siRNA induced apoptosis. This led us to examine whether oridonin-induced apoptosis was mediated by FAS suppression in these cells. We found that oridonin effectively inhibited FAS and SREBP1 mRNA and protein expression in human colorectal cancer cells. In a transient reporter assay, oridonin also reduced transcriptional activity of the FAS promoter region containing the SREBP1 binding site. The FAS inhibition was paralleled by reduction in cellular palmitate and stearic acid. Upregulation of SREBP1 and FAS expression by insulin rescued these cells from oridonin-induced apoptosis.


CONCLUSIONS
These results not only provide a novel molecular mechanism for the anticancer effect of oridonin in colorectal cancer, but also suggest oridonin could be a novel FAS inhibitor in cancer treatment. These results strengthen the scientific basis for the therapeutic use of oridonin in colorectal cancer.
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Hiu-Yee
HY
Kwan
Zhijun
Z
Yang
Wang-Fun
WF
Fong
Yong-Mei
YM
Hu
Zhi-Ling
ZL
Yu
Wen-Luan Wendy
WL
Hsiao
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045786:Diterpenes, Kaurane / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D019308:Palmitic Acid / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013229:Stearic Acids / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; C491901:FAS protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C497387:SREBF1 protein, human; D013229:Stearic Acids; D051780:Sterol Regulatory Element Binding Protein 1; D019014:fas Receptor; C011959:oridonin; D019308:Palmitic Acid; C031183:stearic acid; D064429:Fatty Acid Synthases