Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.
Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.
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DOI：
10.1038/cddis.2013.151
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发表时间：
2013-06-13
影响因子：
9
通讯作者：
Palmieri, M.
中科院分区：
文献类型：
--
作者：
Dando, I.;Donadelli, M.;Costanzo, C.;Pozza, E. Dalla;D'Alessandro, A.;Zolla, L.;Palmieri, M.
大麻素的抗肿瘤作用已在不同的肿瘤系统中描述，包括胰腺癌，但其作用机制仍不清楚。我们使用对CB 1（ACPA）和CB 2（GW）受体特异性的大麻素和代谢组学分析来阐明介导大麻素依赖性抑制胰腺癌细胞生长的潜在途径。用大麻素处理的Panc 1细胞显示由AMP/ATP比率的ROS依赖性增加诱导的AMPK活化升高。ROS促进GAPDH的核转位，其被AMPK进一步放大，从而减弱糖酵解。此外，ROS决定了NADH的积累，提示呼吸链中的阻断，这反过来又抑制了克雷布斯循环。同时，Akt/c-Myc途径的抑制导致丙酮酸激酶亚型M2（PKM 2）的活性降低，进一步下调糖酵解和谷氨酰胺摄取。总之，这些由大麻素介导的胰腺癌细胞代谢的改变导致强烈诱导自噬和抑制细胞生长。
The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear. We used cannabinoids specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake. Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.
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DOI：
10.1042/bj20091372
发表时间：
2010-01-27
期刊：
The Biochemical journal
影响因子：
--
作者：
Fogarty S;Hawley SA;Green KA;Saner N;Mustard KJ;Hardie DG
通讯作者：
Hardie DG
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
37.8
作者：
Lamberts, Regis R.;Onderwater, Geert;Bouwman, R. Arthur
通讯作者：
Bouwman, R. Arthur
影响因子：
5.7
作者：
Qamri Z;Preet A;Nasser MW;Bass CE;Leone G;Barsky SH;Ganju RK
通讯作者：
Ganju RK
影响因子：
12.8
作者：
Kwon, Hyun Jin;Rhim, Ji Heon;Yeo, Eui-Ju
通讯作者：
Yeo, Eui-Ju