Arecoline stimulated Cyr61 production in human gingival epithelial cells: inhibition by lovastatin

Abstract

Cyr61 is associated with growth and progression of many types of tumors and is an independent poor prognostic indicator for oral cancer patients. Areca nut (AN) chewing is the most important etiological factor in the pathogenesis of oral cancer in India and many Southeast Asian countries. Yet, the molecular mechanisms involved in the AN-induced oral cancer remain largely unknown. In this study, we show that arecoline, a main alkaloid found in AN, stimulated Cyr61 synthesis in human gingival epithelial S-G cells. Constitutive overexpression of Cyr61 protein in oral epithelial cells during AN chewing may play a role in the pathogenesis of oral cancer. ERK inhibitor PD98059, N-acetyl-L-cysteine, Rho-associated protein kinase (ROCK) selective inhibitor Y-27632 and a geranylgeranyltransferase inhibitor reduced the arecoline-stimulated levels of Cyr61 protein by ∼31%, 47%, 65% and 100%, respectively. Lovastatin also completely inhibited arecoline-induced Cyr61 synthesis and the inhibition is dose-dependent. Decreased of geranylgeranylated proteins could be the mechanism that lovastatin regulates Cyr61 synthesis and lovastatin could serve as a useful agent in controlling AN-induced oral cancer.