SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer.

Rui Xu,Xin Luo,Qiong Du,Huan Li,Xuan Ye,Qing Zhai,Hongyue Liu

doi:10.3389/fonc.2021.682762

Abstract

Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.

Highlights

Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related morbidity and mortality worldwide
Targeted therapy with Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in Non-small cell lung cancer (NSCLC) patients with EGFR mutation
The current review focused on sirtuin 1 (SIRT1)/PPAR-gamma coactivator 1-alpha (PGC-1a)/ peroxisome proliferator-activated receptor gamma (PPAR-g) as a possible mechanism underlying hypoxia-induced chemoresistance in NSCLC at the epigenetic and metabolic microenvironment level

Summary

Introduction

Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related morbidity and mortality worldwide. A potent DNAdamaging anticancer agent, remains a cornerstone for treating NSCLC, and its major pharmacological effect is to induce cancer cell apoptosis [3, 4]. Targeted molecular therapy is increasingly recognized as a potent strategy in the treatment of NSCLC. EGFR mutations are detected in approximately 15% of all NSCLC patients and are associated with the development of this disease [5, 6]. Targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) has achieved superior efficacy in terms of progression-free survival and overall survival compared with conventional chemotherapy in NSCLC patients with EGFR mutation. Resistance to chemotherapies remain a major cause of treatment failure and disease progression in NSCLC patients [7]

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