Kahweol inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells. (November 2018)

• Record Type: Journal Article
• Authors: Oh, Suck Hoon; Hwang, Yong Pil; Choi, Jae Ho; Jin, Sun Woo; Lee, Gi Ho; Han, Eun Hee; Chung, Young Ho; Chung, Young Chul; Jeong, Hye Gwang
• Is Part Of: Food and chemical toxicology. Volume 121(2018)
• Page Start: 326
• Page End: 335
• Publication Date: 2018-11
• Subjects: Kahweol -- Fatty acid synthase -- HER2 -- Breast cancer -- Proliferation -- Apoptosis; AP-2 Activator protein-2 -- FASN Fatty acid synthase -- HER2 human epidermal growth factor receptor 2 -- GSK3β glycogen synthase kinase-3beta -- mTOR mammalian target of rapamycin -- MAPK mitogen-activated protein kinases -- PARP poly-ADPribose polymerase -- PEA3 polyomavirus enhancer activator 3 -- PI3K phosphatidylinositol 3-kinase -- Akt protein kinase B -- SREBP-1c sterol regulatory element-binding protein-1c; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.09.008
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Kahweol is a coffee-specific diterpene found in the beans of Coffea arabica and has been reported to demonstrate various biological activities, including anti-inflammatory, antioxidant, and apoptotic properties. In the present study, we examined the molecular mechanism of kahweol in human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer cells. Kahweol preferentially inhibited cell proliferation and induced cell death through the induction of a caspase 3-dependent pathway in HER2-overexpression breast cancer cell lines. Kahweol treatment substantially reduced the levels of HER2 protein, mRNA, and transcriptional activity in SKBR3 cells. Kahweol exerts its potent anticancer efficacy by the upregulation of polyomavirus enhancer activator 3 (PEA3) and downregulation of activator protein 2 (AP-2) to inhibit aberrantly activated HER2 signaling. Fatty acid synthase (FASN) expression and sterol regulatory element-binding protein-1c (SREBP-1c) activity were downregulated by kahweol. In addition, kahweol lowered the levels of phosphorylated Akt and its downstream targets mammalian target of rapamycin (mTOR) and cyclin D1. Furthermore, we found that blocking Akt signaling through kahweol treatment significantly reduced FASN expression and subsequently suppressed cell proliferation in HER2-overexpressing cancer cells. Overall, this study suggests that kahweol could be a useful adjuvant therapeutic agent in the treatment of HER2-overexpressing breast cancer. Graphical abstract: Highlights: Kahweol, a coffee-specific diterpene, exhibits anti-tumor effect in HER2-overexpressing cancer cells. Kahweol inhibits proliferation and induces apoptosis through the downregulation of FASN and HER2 expression. Kahweol inhibits HER2 expression and activity through the regulation of PEA3 and AP-2. Kahweol inhibits the phosphorylation of Akt, mTOR, and GSK3β.