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

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.

Synergistic Tumor Inhibition via Energy Elimination by Repurposing Penfluridol and 2-Deoxy-D-Glucose in Lung Cancer

“…PGC-1α is a critical controller of energy metabolism, which is achieved by acting on both mitochondrial biogenesis and OXPHOS in different cancer types including NSCLC [ 36 ]. Ectopic expression of PGC-1α was observed in several cancer types [ 10 ], and the increased expression of PGC-1α was reported to be associated with low survival rates of NSCLC patients [ 37 ].…”

“…These results suggested that the SIRT1/PGC-1α axis may facilitate NSCLC growth by promoting mitochondrial biogenesis, and penfluridol is a potential inhibitor for blocking this pathway. Moreover, previous studies indicated that chemotherapy of cancers induced an SIRT1/PGC-1α axis-dependent increase in OXPHOS that promoted tumor survival against chemotherapeutic drugs [ 12 , 36 ], suggesting that penfluridol exhibits the potential to increase the chemosensitivity of NSCLC cells, and this issue should be further investigated. In addition to SIRT1, our results showed that another PGC-1α regulator, p53, was also inhibited by penfluridol in A549 cells.…”

Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

“…Hypoxia is common phenomena in solid tumors, and deprivation of oxygen and nutrients under this situation make a small subgroup of cancer cells in the inner tumors more aggressiveness ( 16 – 18 ) and even resistant to chemical drugs ( 19 , 52 – 55 ). For example, Liu et al.…”

“…evidence that hypoxia facilitates chemoresistance in glioma ( 19 ), Xu et al. report that hypoxia induces chemoresistance in non-small cell lung cancer (NSCLC) ( 55 ), and Zhu et al. find that cisplatin-resistance in esophageal cancer cells was also enhanced by hypoxic conditions ( 54 ).…”

Emerging Nano-Based Strategies Against Drug Resistance in Tumor Chemotherapy

“…Evidence has revealed that hypoxia in the tumor microenvironment has a crucial role in the clinical resistance of chemotherapy through a variety of signal transduction pathways and molecular changes ( Pastorek and Pastorekova, 2015 ; Wang D. et al, 2021 ; Xu et al, 2021 ). The development of advanced nanomaterial delivery methods for reversing the resistance of hypoxic tumors is therefore of great interest but remains a considerable challenge.…”