Reactive Oxygen Species Dependent Phosphorylation of the Liver Kinase B1/AMP Activated Protein Kinase/ Acetyl-CoA Carboxylase Signaling is Critically Involved in Apoptotic Effect of Lambertianic Acid in Hepatocellular Carcinoma Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Oct 21

PMID 29050265

Citations 6

Authors

Arong Jeong

Ju-Ha Kim

Hyo-Jung Lee

Sung-Hoon Kim

Affiliations

Soon will be listed here.

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 MEF cells, but not in 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.

Citing Articles

GAS6/Axl is associated with AMPK activation and attenuates HO-induced oxidative stress.

Liang Z, Yang Y, Wu X, Lu C, Zhao H, Chen K Apoptosis. 2022; 28(3-4):485-497.

PMID: 36580193 DOI: 10.1007/s10495-022-01801-5.

Roles of AMPK and Its Downstream Signals in Pain Regulation.

Wang S, Dai Y Life (Basel). 2021; 11(8).

PMID: 34440581 PMC: 8401922. DOI: 10.3390/life11080836.

Short Overview of ROS as Cell Function Regulators and Their Implications in Therapy Concepts.

Milkovic L, cipak Gasparovic A, Cindric M, Mouthuy P, Zarkovic N Cells. 2019; 8(8).

PMID: 31366062 PMC: 6721558. DOI: 10.3390/cells8080793.

Suppression of STAT3 Phosphorylation and RelA/p65 Acetylation Mediated by MicroRNA134 Plays a Pivotal Role in the Apoptotic Effect of Lambertianic Acid.

Sim D, Lee H, Jung J, Im E, Hwang J, Kim D Int J Mol Sci. 2019; 20(12).

PMID: 31248140 PMC: 6628272. DOI: 10.3390/ijms20122993.

The role of acetyl-coA carboxylase2 in head and neck squamous cell carcinoma.

Li K, Zhang C, Chen L, Wang P, Fang Y, Zhu J PeerJ. 2019; 7:e7037.

PMID: 31218122 PMC: 6568254. DOI: 10.7717/peerj.7037.

References

Bruix J, Gores G, Mazzaferro V . Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014; 63(5):844-55. PMC: 4337888. DOI: 10.1136/gutjnl-2013-306627. View

Cho S, Cho S, Park E, Kim B, Sohn E, Oh B . Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells. Bioorg Med Chem Lett. 2014; 24(11):2560-4. DOI: 10.1016/j.bmcl.2014.03.084. View

Epifano F, Genovese S, Miller R, Majumdar A . Auraptene and its effects on the re-emergence of colon cancer stem cells. Phytother Res. 2012; 27(5):784-6. PMC: 3496036. DOI: 10.1002/ptr.4773. View

Wu S, Wu Y, Wu T, Wei Y . Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta. 2014; 1840(4):1331-44. DOI: 10.1016/j.bbagen.2013.10.034. View

Garrido C, Galluzzi L, Brunet M, Puig P, Didelot C, Kroemer G . Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006; 13(9):1423-33. DOI: 10.1038/sj.cdd.4401950. View

Chae H, Chin Y . Anti-allergic effect of lambertianic acid from Thuja orientalis in mouse bone marrow-derived mast cells. Immunopharmacol Immunotoxicol. 2011; 34(2):250-5. DOI: 10.3109/08923973.2011.600763. View

Song P, Wang S, He C, Wang S, Liang B, Viollet B . AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circ Res. 2011; 109(11):1230-9. PMC: 3235405. DOI: 10.1161/CIRCRESAHA.111.250423. View

Pramanik K, Fofaria N, Gupta P, Srivastava S . CBP-mediated FOXO-1 acetylation inhibits pancreatic tumor growth by targeting SirT. Mol Cancer Ther. 2014; 13(3):687-98. PMC: 3954235. DOI: 10.1158/1535-7163.MCT-13-0863. View

Qi D, Young L . AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol Metab. 2015; 26(8):422-9. PMC: 4697457. DOI: 10.1016/j.tem.2015.05.010. View

10.

Cheng K, Wong C, Mattheolabakis G, Xie G, Huang L, Rigas B . Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics. Int J Oncol. 2013; 43(3):895-902. PMC: 3787887. DOI: 10.3892/ijo.2013.1995. View

11.

Avgustinovich D, Fomina M, Sorokina I, Tolstikova T . Complex investigation of the effects of lambertianic acid amide in female mice under conditions of social discomfort. Bull Exp Biol Med. 2014; 157(5):583-7. DOI: 10.1007/s10517-014-2621-y. View

12.

Sekiguchi H, Takabayashi F, Irie K, Murakami A . Auraptene attenuates gastritis via reduction of Helicobacter pylori colonization and pro-inflammatory mediator production in C57BL/6 mice. J Med Food. 2012; 15(7):658-63. DOI: 10.1089/jmf.2011.1844. View

13.

Rehman G, Shehzad A, Khan A, Hamayun M . Role of AMP-activated protein kinase in cancer therapy. Arch Pharm (Weinheim). 2014; 347(7):457-68. DOI: 10.1002/ardp.201300402. View

14.

Jiang Y, Lei J, Feng F, Liang Q, Wang F . Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation. Acta Pharmacol Sin. 2014; 35(12):1556-65. PMC: 4261125. DOI: 10.1038/aps.2014.88. View

15.

Green D, Llambi F . Cell Death Signaling. Cold Spring Harb Perspect Biol. 2015; 7(12). PMC: 4665079. DOI: 10.1101/cshperspect.a006080. View

16.

Alkhalaf M . Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology. 2007; 80(2-3):134-43. DOI: 10.1159/000103253. View

17.

de Medina P, Genovese S, Paillasse M, Mazaheri M, Caze-Subra S, Bystricky K . Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors. Mol Pharmacol. 2010; 78(5):827-36. DOI: 10.1124/mol.110.065250. View

18.

Kleinberg L, Davidson B . Cell survival and apoptosis-related molecules in cancer cells in effusions: a comprehensive review. Diagn Cytopathol. 2009; 37(8):613-24. DOI: 10.1002/dc.21095. View

19.

You O, Kim S, Kim B, Sohn E, Lee H, Shim B . Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells. Bioorg Med Chem Lett. 2013; 23(9):2692-5. DOI: 10.1016/j.bmcl.2013.02.080. View

20.

Soltani F, Mosaffa F, Iranshahi M, Karimi G, Malekaneh M, Haghighi F . Auraptene from Ferula szowitsiana protects human peripheral lymphocytes against oxidative stress. Phytother Res. 2009; 24(1):85-9. DOI: 10.1002/ptr.2874. View