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

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

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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 ...

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    Key Points
    • Conclusion/Relevance: “We speculate that SIRT1/PGC-1α/PPAR-γ signaling may represent a molecular metabolic mechanism underlying hypoxia-induced chemoresistance in the NSCLC microenvironment, and targeting hypoxia-related metabolic adaptation may be a potential therapeutic strategy for overcoming chemoresistance in NSCLC.”
    • The acetylation of transcription factors plays a pivotal role in tumorigenesis and drug resistance. This role is independent of histone modifications. In addition to being an intermediary in cellular metabolism in gene silencing/aging, SIRT1 is a chief regulator of various intracellular biological processes, such as energy metabolism, DNA damage responses, the maintenance of genome stability, and tumorigenesis. SIRT1 could be related to the susceptibility of the elderly to hypoxic injury, which results in cell death by means of energy depletion and increased oxidative stress.
    • The review authors wrote, “Metabolic stress and biosynthetic stress are key factors affecting the NAD+ pool and NAD+-dependent SIRT1 activity. In the context of hypoxia-induced chemoresistance, SIRT1-dependent deacetylation may be primarily related to its ability to target and modulate the activity of signal transduction pathways and transcription factors such as P53, PPARs, PGC-1α, AMPK, FOXO proteins, and NF-κB.”
    • Other points that the authors made were that epigenetic modification may facilitate primary resistance and play a role in acquired resistance during immunotherapy via its extensive impact on many facets of antitumor immunity. Additionally, the mitochondrion is novel therapeutic target in tumor cells and makes a particularly enviable target under hypoxic condition.