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

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

doi:10.18632/oncotarget.11526

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.

Highlights

NAD(P)H: quinone oxidoreductase 1 (NQO1), a flavin protease enzyme prevalent in most eukaryotic cells, has attracted considerable attention because of important roles in cancer chemoprevention and oncotherapy [1]
Since FOXO6 is dominantly expressed in brain [22], we examined the changes of FOXO1, FOXO3 and FOXO4 levels in response to NQO1 activation by Tanshinone IIA (TSA) and β-lap in NQO1-highly expressed A549 cells
We demonstrated that L-type amino acid transporter 1 (LAT1) mediated uptake of tryptophan and subsequent de-novo synthesis of NAD+ is important for NSCLC cells to combat against NQO1 bioactivationinduced cell apoptosis

Summary

Introduction

NAD(P)H: quinone oxidoreductase 1 (NQO1), a flavin protease enzyme prevalent in most eukaryotic cells, has attracted considerable attention because of important roles in cancer chemoprevention and oncotherapy [1]. The FDA of U.S.A has approved a panel of phase II clinical trials for testing the chemotherapeutic efficacies of β-lapachone (β-lap), an NQO1 targeting agent, either alone or in combinatory use with other marketed chemotherapeutic drugs. It has been well verified that such NQO1 targeting agents induce cell death largely due to bioreduction triggered futile redox cycle [6]. The specific mechanism of how cancer cells sense NQO1-triggered redox conditions and thereafter initiating apoptotic and/or necroptotic cell death remains largely elusive. This represents a major bottleneck in successful development of NQO1 activation agents to chemotherapeutic drugs

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