title: MnSOD overexpression confers cisplatin resistance in lung adenocarcinoma via the NF-κB/Snail/Bcl-2 pathway.
abstract: Manganese superoxide dismutase (MnSOD) has been shown to be associated with doxorubicin resistance in gastric cancer cells, but the underlying mechanism of MnSOD in drug resistance remains unclear. A recent study indicated that NF-κB activation by MnSOD promoted tumor malignancy in lung adenocarcinoma. Therefore, we hypothesized that MnSOD-mediated NF-κB activation might confer cisplatin resistance in lung adenocarcinoma via the NF-κB/Bcl-2/Snail pathway. Here, the inhibition concentration of cisplatin with 50% cell viability (IC50) was positively correlated with MnSOD expression and its activity in a panel of lung adenocarcinoma cells. The IC50 value was markedly increased and decreased by MnSOD overexpression and knockdown, respectively, in lung cancer cells. Mechanistically, an increase in Bcl-2 by MnSOD-mediated NF-κB activation confers greater cisplatin resistance than cIAP2, Bcl-xL, Mcl-1, and Snail. MnSOD-mediated cisplatin resistance can be overcome by a Bcl-2 antagonist (ABT-199) or IKKβ inhibitor (curcumin) in cells and xenograft tumors. MnSOD expression was positively correlated with nuclear p65 protein and Bcl-2 mRNA expression in tumors from patients with lung adenocarcinomas. A retrospective study indicated that it was more common for MnSOD-positive, nuclear p65-positive, or high Bcl-2 mRNA tumors to have an unfavorable response to cisplatin-based chemotherapy than their counterparts. Therefore, we suggest that ABT-199 or curcumin may be potentially useful to improve tumor regression and chemotherapeutic response in patients with MnSOD/Bcl-2-positive tumors.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 115, Taiwan.
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 115, Taiwan.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 115, Taiwan. Electronic address: hl@tmu.edu.tw.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000071250:Snail Family Transcription Factors; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D013482:Superoxide Dismutase; D002945:Cisplatin
keywords: Cisplatin; Free radicals; IKKβ/NF-κB; Lung adenocarcinoma; MnSOD