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

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-1 alpha, peroxisome proliferator-activated receptor gamma (PPAR-gamma), and PPAR-gamma coactivator 1-alpha (PGC-1 alpha) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1 alpha 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-1 alpha/PPAR-gamma 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.

Automated summary

Resistance to treatment in non-small cell lung cancer (NSCLC) is often driven by hypoxia, which can induce molecular metabolic adaptations leading to chemotherapy resistance. Molecular mediators like SIRT1/PGC-1 alpha/PPAR-gamma play a role in regulating mitochondrial function in response to hypoxia, affecting chemoresistance in NSCLC. Targeting hypoxia-related metabolic adaptations may be a promising therapeutic strategy to overcome drug resistance in NSCLC.