Research Papers:

De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells

Huiying Liu, Rong Xing, Xuefang Cheng, Qingran Li, Fang Liu, Hui Ye, Min Zhao, Hong Wang, Guangji Wang _ and Haiping Hao

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Oncotarget. 2016; 7:62503-62519. https://doi.org/10.18632/oncotarget.11526

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Huiying Liu1,2,*, Rong Xing1,3,*, Xuefang Cheng1, Qingran Li1, Fang Liu1, Hui Ye1, Min Zhao1, Hong Wang1, Guangji Wang1, Haiping Hao1

1State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China

2Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing 100191, China

3Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China

*These authors have contributed equally to this work

Correspondence to:

Guangji Wang, email: [email protected]

Haiping Hao, email: [email protected]

Keywords: NQO1, FOXO1, SIRT1, NAD+, LAT1

Received: December 15, 2015     Accepted: August 08, 2016     Published: August 23, 2016


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.

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