title: De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells.
abstract: Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress.
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.|Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, China.
authors: Huiying
authors: H
authors: Liu
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.|Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China.
authors: Rong
authors: R
authors: Xing
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Xuefang
authors: X
authors: Cheng
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Qingran
authors: Q
authors: Li
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Fang
authors: F
authors: Liu
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Hui
authors: H
authors: Ye
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Min
authors: M
authors: Zhao
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Hong
authors: H
authors: Wang
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Guangji
authors: G
authors: Wang
authors: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
authors: Haiping
authors: H
authors: Hao
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009243:NAD / Q000096:biosynthesis*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D027283:Large Neutral Amino Acid-Transporter 1; D009243:NAD; D014364:Tryptophan; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D010100:Oxygen
keywords: FOXO1; LAT1; NAD+; NQO1; SIRT1