We summarize the literature relating to the development of hypoxia-induced chemotherapy resistance in Non-small cell lung cancer, focusing on the putative epigenetic and metabolic microenvironmental mechanisms
2021
Key concepts
- ATP-binding cassette
- hypoxia
- PPAR-γ
- immunotherapy
- Cardiovascular disease
- Small cell lung cancer
- Hypoxia-inducible factors
- non-small cell lung cancer
- SIRT1
- apoptosis
- Histone deacetylase
- PPAR-g
- reactive oxygen species
- oxidative phosphorylation
- metabolic adaptation
- epidermal growth factor receptor
- vascular endothelial growth factor
- PGC-1a
- Adenosine monophosphate activated protein kinase
- sirtuin 1
- cisplatin
- nuclear factor-kappa B
- chemotherapy
- tumor microenvironment
- Nicotinamide adenine dinucleotide
- tyrosine kinase inhibitor
- epithelial–mesenchymal transition
Scholarcy highlights
- Lung cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related morbidity and mortality worldwide
- A study investigating the development of Non-small cell lung cancer resistance to Epidermal growth factor receptor-tyrosine kinase inhibitors found that gefitinib-resistant NSCLC cells acquire metabolic flexibility characterized as a ligand-independent translocation of EGFR to mitochondria, which might contribute to the upregulation of mitochondrial function and capacity for oxidative phosphorylation. These observations indicate that the dependence on mitochondrial OXPHOS is a recurrent mechanism of cancer resistance to cisplatin treatment, while Peroxisome proliferator—activated receptor-g coactivator-1a-mediated enhancement of mitochondrial biogenesis and OXPHOS is crucial for the development of chemoresistance in NSCLC under hypoxic conditions
- Hypoxic microenvironment might inhibit the activation of Adenosine monophosphate activated protein kinase targets, as well as apoptosis, by decreasing PGC-1a through sirtuin 1 deacetylation-dependent mechanisms; which may regulate the cytotoxic response to cisplatin and doxorubicin by licensing an apoptotic process controlled by mitochondria in NSCLC
- The current review focused on SIRT1/PGC-1a/ Peroxisome proliferator activated receptor-g as a possible mechanism underlying hypoxia-induced chemoresistance in NSCLC at the epigenetic and metabolic microenvironment level
- This review offers a preclinical proofof-concept for the targeting of the SIRT1/PPAR-g/PGC-1a signaling pathway
- Targeting signaling pathways of cancer metabolic dependency under hypoxia microenvironment could be explored as a new therapeutic combination strategy for overcoming chemoresistance in NSCLC
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