title: SIRT5 facilitates cancer cell growth and drug resistance in non-small cell lung cancer.
abstract: Lung cancer is one of the leading causes of cancer-related death in developed countries. Despite decades of intensive efforts to comate this malignant disease, the prognosis of lung cancer remains unfavorable and is especially poor in advanced non-small cell lung cancer (NSCLC). Accumulating evidence indicate that one of the main causes of the poor outcome in NSCLC treatment is the innate resistance of NSCLC patients to anticancer drugs. However, the mechanism underling NSCLC development and drug resistance is not fully understood. Here we show that the mitochondrial class III NAD(+)-dependent deacetylase SIRT5 is overexpressed in human NSCLC and high expression of SIRT5 predicts poor survival. SIRT5 knockdown represses lung cancer cell growth and transformation in vitro and in vivo. Furthermore, we find that SIRT5 knockdown makes lung cancer cells more sensitive to drug (cis-diamminedichloroplatinum [CDDP], 5-fluorouracil [5-FU] or bleomycin) treatment in vitro and in vivo. Mechanically, we identify Nrf2, which is a core transcription factor for lung cancer growth and drug resistance, as a target of SIRT5. SIRT5 mRNA level is positively correlated with the expression of Nrf2 in lung cancer tissues and SIRT5 knockdown reduces the expression of Nrf2 and its downstream drug-resistance genes. Taken together, our findings implicate that SIRT5 as a protein responsible for growth and drug resistance in human NSCLC, and SIRT5 may serve as a potential prognostic factor and drug target for intervention.
authors: Department of Oncology, Jiangsu Zhangjiagang City First People's Hospital, Zhangjiagang City Hospital Affiliated to Suzhou University, Zhangjiagang, 215699, China.
authors: Weidong
authors: W
authors: Lu
authors: Yun
authors: Y
authors: Zuo
authors: Yufang
authors: Y
authors: Feng
authors: Min
authors: M
authors: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; C508544:SIRT5 protein, human; D037761:Sirtuins; D002945:Cisplatin; D005472:Fluorouracil