Abstract
Though lambertianic acid (LA) is reported to have hypolipidemic activity in liver, its underlying anticancer mechanism is poorly understood so far. Thus, in the present study, apoptotic mechanism of LA was elucidated in HepG2 and SK-Hep1 hepatocellular carcinoma (HCC) cells. Here LA increased cytotoxicity, sub-G1 population and Annexin V/PI positive cells in two HCC cells. Also, LA cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), activated phosphorylation of liver kinase B1 (LKB1)/AMP activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC) pathway and also suppressed antiapoptotic proteins such as phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and the expression of B cell lymphoma-2 (Bcl-2)/ B-cell lymphoma-extra large (Bcl-xL) and cyclooxygenase-2 (COX-2) in two HCC cells. Furthermore, LA generated reactive oxygen species (ROS) in HepG2 cells and AMPK inhibitor compound C or ROS inhibitor N-acetyl-L-cysteine (NAC) blocked the apoptotic ability of LA to cleave PARP or increase sub G1 population in HepG2 cells. Consistently, cleavages of PARP and caspase-3 were induced by LA only in AMPK+/+ MEF cells, but not in AMPK-/- MEF cells. Also, immunoprecipitation (IP) revealed that phosphorylation of LKB1/AMPK through their binding was enhanced in LA treated HepG2 cells. Overall, these findings suggest that ROS dependent phosphorylation of LKB1/AMPK/ACC signaling is critically involved in LA induced apoptosis in HCCs.
Highlights
Hepatocellular carcinoma (HCC) is approximately 90% of all cases of primary liver cancer, the 5th most common cancer worldwide and the third leading cause of cancer-related mortality [1, 2]
These findings suggest that reactive oxygen species (ROS) dependent phosphorylation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling is critically involved in lambertianic acid (LA) induced apoptosis in hepatocellular carcinoma (HCC)
To confirm whether the apoptotic effect of LA is related to AMPK signaling, Western blotting was performed in LA treated HCC cells with antibodies of p-LKB1, p-AMPK and p-ACC
Summary
Hepatocellular carcinoma (HCC) is approximately 90% of all cases of primary liver cancer, the 5th most common cancer worldwide and the third leading cause of cancer-related mortality [1, 2]. AMPK activation is a therapeutic target for the prevention and treatment of cancer by metformin and other anticancer agents. Though labmertianic acid (LA) is known to have anti-obesity [40], stress-protective [41], anti-allergic [42] and neurotropic [43, 44] activities, its other anti-cancer studies have not been reported except our group’s report on anticancer effect of LA via androgen receptor(AR) ablation [45] inhibition until now. In the current study, the underlying apoptotic mechanism of LA was elucidated in association with reactive oxygen species(ROS) and liver kinase B1 (LKB1)/AMP activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling pathway in HCCs
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