Endogenous AMPKα2 Mediates the Inhibition of Biliary Fibroblasts Proliferation

Abstract

Background: Although it has been established that activating adenosine monophosphate-activated protein kinase (AMPK) inhibits cell proliferation in several cells, it is unknown whether AMPK is involved in inhibiting biliary fibroblast growth. Objective: To specifically investigate the influence of AMPK isoforms on proliferation. Method: To further address its underlying molecular mechanisms, primary cultured rat biliary fibroblasts were transfected with sequence-specific AMPK1 or AMPK2 siRNA. Results: Our findings show that knocking down AMPK2 greatly increased the proliferation of primary cultured biliary fibroblasts, accompanied by the activation of mTOR, an increase in S-phase kinase-associated protein 2 (Skp2) expression, and a decrease in p27 protein levels. AMPK2 inhibition-triggered Skp2 overexpression and concomitant p27 decrease, as well as biliary fibroblast proliferation, were reversed by rapamycin inhibition or previous silencing of Skp2 production by targeted small interfering RNA (siRNA) transfection. Conclusion: We concluded that AMPK2 regulates the mTOR/Skp2/p27 signaling pathway and so causes endogenous suppression of primary cultured biliary fibroblast growth. The reduction of biliary fibroblast proliferation by AMPK2 could be a potential method in treating benign biliary stricture (BBS).