期刊
PLOS ONE
卷 9, 期 12, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0114573
关键词
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资金
- National Institutes of Health [P01 CA163200, P30 DK4130, R01 DK100405]
- Department of Veterans Affair Grant [1I01BX001473]
- Ronald S. Hirschberg Chair of Pancreatic Cancer Research
Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Here, we show that treatment of pancreatic ductal adenocarcinoma (PDAC) cells (PANC-1, MiaPaCa-2) with the isoquinoline alkaloid berberine (0.3-6 mu M) inhibited DNA synthesis and proliferation of these cells and delay the progression of their cell cycle in G1. Berberine treatment also reduced (by 70%) the growth of MiaPaCa-2 cell growth when implanted into the flanks of nu/nu mice. Mechanistic studies revealed that berberine decreased mitochondrial membrane potential and intracellular ATP levels and induced potent AMPK activation, as shown by phosphorylation of AMPK alpha subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser(79). Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr(389) and S6 at Ser(240/244)) and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of alpha(1) and alpha(2) catalytic subunit expression of AMPK reversed the inhibitory effect produced by treatment with low concentrations of berberine on mTORC1, ERK and DNA synthesis in PDAC cells. However, at higher concentrations, berberine inhibited mitogenic signaling (mTORC1 and ERK) and DNA synthesis through an AMPK-independent mechanism. Similar results were obtained with metformin used at doses that induced either modest or pronounced reductions in intracellular ATP levels, which were virtually identical to the decreases in ATP levels obtained in response to berberine. We propose that berberine and metformin inhibit mitogenic signaling in PDAC cells through dose-dependent AMPK-dependent and independent pathways.
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