title: Inhibition of lipolysis by mercaptoacetate and etomoxir specifically sensitize drug-resistant lung adenocarcinoma cell to paclitaxel.
abstract: Chemoresistance is a major cause of treatment failure in patients with lung cancer. Although the extensive efforts have been made in overcoming chemoresistance, the underlying mechanisms are still elusive. Cancer cells reprogram cellular metabolism to satisfy the demands of malignant phenotype. To reveal roles of cancer metabolism in regulating chemoresistance, we profiled the metabolic characteristics in paclitaxel-resistant lung cancer cells by flux assay. Glucose and oleate metabolism were significantly different between resistant and non-resistant cells. In addition, targeting metabolism as a strategy to overcome drug resistance was investigated using specific metabolic inhibitors. Inhibition of glycolysis and oxidative phosphorylation by 2-deoxyglucose and malonate, respectively, potentiated the effects of paclitaxel on nonresistant lung adenocarcinoma cells but not paclitaxel-resistant cells. By contrast, inhibition of lipolysis by mercaptoacetate or etomoxir synergistically inhibited drug-resistant lung adenocarcinoma cell proliferation. We conclude that lipolysis inhibition potentially be a therapeutic strategy to overcome drug resistance in lung cancer.
authors.affiliation: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiajin
authors.initials: J
authors.lastname: Li
authors.forename: Shiyan
authors.initials: S
authors.lastname: Zhao
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Teng
authors.initials: T
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Ping
authors.initials: P
authors.lastname: Miao
authors.forename: Shaoli
authors.initials: S
authors.lastname: Song
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017239:Paclitaxel / Q000494:pharmacology*; D013864:Thioglycolates / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D013864:Thioglycolates; D002245:Carbon Dioxide; D019301:Oleic Acid; C017487:2-mercaptoacetate; D005947:Glucose; C054207:etomoxir; D017239:Paclitaxel
references.citation: Cancer Genomics Proteomics. 2012 Sep-Oct;9(5):275-86
references.pmid: 22990107
references.citation: Pharmacogenomics. 2012 Jul;13(9):1073-86
references.pmid: 22838953
references.citation: Free Radic Biol Med. 2010 Apr 15;48(8):1024-33
references.pmid: 20083194
references.citation: Curr Opin Cell Biol. 2006 Dec;18(6):598-608
references.pmid: 17046224
references.citation: PLoS One. 2012;7(9):e46484
references.pmid: 23029529
references.citation: Toxicol In Vitro. 2011 Dec;25(8):1581-7
references.pmid: 21664962
references.citation: Cancer Res. 2004 Jan 1;64(1):31-4
references.pmid: 14729604
references.citation: Nat Rev Cancer. 2013 Apr;13(4):227-32
references.pmid: 23446547
references.citation: J Reprod Fertil. 1977 Mar;49(2):261-6
references.pmid: 557551
references.citation: J Clin Invest. 2010 Jan;120(1):142-56
references.pmid: 20038799
references.citation: J Cancer Res Clin Oncol. 2011 Mar;137(3):521-32
references.pmid: 20499251
references.citation: Cancer Res. 2011 Jul 1;71(13):4585-97
references.pmid: 21498634
references.citation: Genes Dev. 2011 May 15;25(10):1041-51
references.pmid: 21576264
references.citation: Oncogene. 2011 Jan 20;30(3):253-64
references.pmid: 20972457
references.citation: Methods Enzymol. 2009;463:305-28
references.pmid: 19892179
references.citation: J Clin Invest. 2012 Jul;122(7):2417-27
references.pmid: 22684109
references.citation: Cancer Cell. 2010 Sep 14;18(3):207-19
references.pmid: 20832749
references.citation: Br J Cancer. 2013 Jan 15;108(1):72-81
references.pmid: 23257894
references.citation: PLoS One. 2013 May 14;8(5):e63965
references.pmid: 23691130
references.citation: Cell Biol Toxicol. 2011 Oct;27(5):363-70
references.pmid: 21706388
references.citation: Int J Cancer. 2008 Jul 15;123(2):476-483
references.pmid: 18452174
references.citation: Cell Death Dis. 2013 Mar 07;4:e532
references.pmid: 23470539
references.citation: Oncogene. 2013 Nov 14;32(46):5315-30
references.pmid: 23474753
references.citation: Biochem J. 1982 Jul 15;206(1):53-9
references.pmid: 7126196
references.citation: Nat Rev Drug Discov. 2011 Aug 31;10(9):671-84
references.pmid: 21878982
references.citation: FASEB J. 2002 Oct;16(12):1550-7
references.pmid: 12374777
references.citation: Oncogene. 2006 Aug 7;25(34):4633-46
references.pmid: 16892078
references.citation: Mol Cell Proteomics. 2010 Mar;9(3):457-70
references.pmid: 20026476
references.citation: Biochem J. 1983 Dec 1;215(3):457-64
references.pmid: 6661181
references.citation: Cytotechnology. 2007 May;54(1):1-4
references.pmid: 19003012
references.citation: Front Pharmacol. 2013 Mar 14;4:28
references.pmid: 23504227