title: FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.
abstract: Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: D-W
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
authors.forename: M-C
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: N-Y
authors.initials: NY
authors.lastname: Hsu
authors.affiliation: 1] Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC [2] School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: 1] Division of Thoracic Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan, ROC [2] Department of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: 1] Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC [2] School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002945:Cisplatin; D009363:Neoplasm Proteins; D009570:Nitriles; D010767:Phosphorylcholine; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D013450:Sulfones; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000099170:Bis(5'-adenosyl)triphosphatase; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C438378:BBC3 protein, human; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C105905:perifosine