Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells.
Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells.
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胰腺癌细胞中Berberine和二甲双胍抑制MTORC1，ERK，DNA合成和增殖的剂量依赖性AMPK依赖性和独立机制。
DOI：
10.1371/journal.pone.0114573
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rozengurt E
中科院分区：
文献类型：
--
作者：
Ming M;Sinnett-Smith J;Wang J;Soares HP;Young SH;Eibl G;Rozengurt E
天然产物代表了具有抗增殖和化学预防特性的潜在小化学分子的丰富储存库。在这里，我们发现用异喹啉生物碱小檗碱（0.3-6 µM）处理胰腺导管腺癌（PDAC）细胞（PANC-1，MiaPaCa-2）抑制了这些细胞的DNA合成和增殖，并延迟了G1期细胞周期的进展。当植入nu/nu小鼠的侧腹时，小檗碱处理也减少了MiaPaCa-2细胞生长的生长（70%）。机制研究表明，小檗碱降低线粒体膜电位和细胞内ATP水平，并诱导有效的AMPK激活，如AMPK α亚基在Thr-172和乙酰辅酶A羧化酶（ACC）在Ser 79的磷酸化所示。此外，小檗碱剂量依赖性地抑制mTORC 1（磷酸化的S6 K在Thr 389和S6在Ser 240/244）和ERK激活的PDAC细胞刺激的胰岛素和神经降压素或胎牛血清。抑制AMPK α1和α2催化亚基表达可逆转低浓度小檗碱对PDAC细胞mTORC 1、ERK和DNA合成的抑制作用。然而，在较高浓度下，小檗碱通过AMPK非依赖性机制抑制促有丝分裂信号传导（mTORC 1和ERK）和DNA合成。在诱导细胞内ATP水平适度或显著降低的剂量下使用二甲双胍获得了类似的结果，这与小檗碱引起的ATP水平降低几乎相同。我们认为小檗碱和二甲双胍通过剂量依赖性AMPK依赖性和非依赖性途径抑制PDAC细胞中的促有丝分裂信号。
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 µM) 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 α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser79. Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr389 and S6 at Ser240/244) and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of α1 and α2 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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影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
4.8
作者：
El-Mir, MY;Nogueira, V;Leverve, X
通讯作者：
Leverve, X
影响因子：
4.5
作者：
Domitrovic, Robert;Jakovac, Hrvoje;Blagojevic, Gordana
通讯作者：
Blagojevic, Gordana
影响因子：
64.5
作者：
Inoki, Ken;Ouyang, Hongjiao;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang