cyclin-d1 and kahweol

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.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Diterpenes; Down-Regulation; Fatty Acid Synthase, Type I; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Humans; Molecular Structure; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; TOR Serine-Threonine Kinases

Kahweol as a coffee-specific diterpene has been reported to exert anti-cancer properties. However, the mechanism responsible for the anti-cancer effects of kahweol is not fully understood. The main aim of this investigation was to determine the effect of kahweol on cell proliferation and the possible mechanisms in human colorectal cancer cells. Kahweol inhibited markedly the proliferation of human colorectal cancer cell lines such as HCT116, SW480. Kahweol decreased cyclin D1 protein level in HCT116 and SW480 cells. Contrast to protein levels, cyclin D1 mRNA level and promoter activity did not be changed by kahweol treatment. MG132 treatment attenuated kahweol-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in kahweol-treated cells. Kahweol increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated cyclin D1 degradation by kahweol. Inhibition of ERK1/2 by PD98059, JNK by SP600125 or GSK3β by LiCl suppressed cyclin D1 phosphorylation and downregulation by kahweol. Furthermore, the inhibition of nuclear export by LMB attenuated cyclin D1 degradation by kahweol. In conclusion, kahweol-mediated cyclin D1 degradation may contribute to the inhibition of the proliferation in human colorectal cancer cells.

Topics: Antineoplastic Agents; Blotting, Western; Cell Proliferation; Coffee; Colorectal Neoplasms; Cyclin D1; Diterpenes; Glycogen Synthase Kinase 3 beta; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Phosphorylation; Proteasome Endopeptidase Complex; Proteolysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Threonine; Tumor Cells, Cultured