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

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Aug 12

PMID 34381712

Citations 23

Authors

Rui Xu

Xin Luo

Xuan Ye

Huan Li

Hongyue Liu

Qiong Du

Qing Zhai

Affiliations

Soon will be listed here.

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.

Citing Articles

Harnessing the FOXO-SIRT1 axis: insights into cellular stress, metabolism, and aging.

Gupta S, Afzal M, Agrawal N, Almalki W, Rana M, Gangola S Biogerontology. 2025; 26(2):65.

PMID: 40011269 DOI: 10.1007/s10522-025-10207-0.

Silencing of LINC01278 promotes sensitivity of non-small cell lung cancer cells to osimertinib by targeting miR-324-3p/ZFX axis.

Lei Q, Liu P, Guan X, Liu L, He W Cytotechnology. 2024; 77(1):23.

PMID: 39711969 PMC: 11659544. DOI: 10.1007/s10616-024-00673-8.

Spatially resolved subcellular protein-protein interactomics in drug-perturbed lung-cancer cultures and tissues.

Cai S, Hu T, Venkataraman A, Moctezuma F, Ozturk E, Zhang N Nat Biomed Eng. 2024; .

PMID: 39478233 DOI: 10.1038/s41551-024-01271-x.

Machine learning-derived peripheral blood transcriptomic biomarkers for early lung cancer diagnosis: Unveiling tumor-immune interaction mechanisms.

Li X, Li X, Qin J, Lei L, Guo H, Zheng X Biofactors. 2024; 51(1):e2129.

PMID: 39415336 PMC: 11681315. DOI: 10.1002/biof.2129.

Protein posttranslational modifications in metabolic diseases: basic concepts and targeted therapies.

Yang Y, Wu J, Zhou W, Ji G, Dang Y MedComm (2020). 2024; 5(10):e752.

PMID: 39355507 PMC: 11442990. DOI: 10.1002/mco2.752.

References

Scanlon S, Glazer P . Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair (Amst). 2015; 32:180-189. PMC: 4522377. DOI: 10.1016/j.dnarep.2015.04.030. View

Wang M, Li G, Yang Z, Wang L, Zhang L, Wang T . Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer. Oncotarget. 2017; 8(5):8083-8094. PMC: 5352384. DOI: 10.18632/oncotarget.14097. View

Yan L, Zhao Q, Liu L, Jin N, Wang S, Zhan X . Expression of SIRT1 and survivin correlates with poor prognosis in esophageal squamous cell carcinoma. Medicine (Baltimore). 2020; 99(34):e21645. PMC: 7447426. DOI: 10.1097/MD.0000000000021645. View

Huang C, Hsu L, Chen C, Chang G, Chang H, Hung Y . Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy. Cancers (Basel). 2020; 12(1). PMC: 7017237. DOI: 10.3390/cancers12010181. View

Wang D, Zhao C, Xu F, Zhang A, Jin M, Zhang K . Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics. 2021; 11(6):2860-2875. PMC: 7806469. DOI: 10.7150/thno.51797. View

Jin Q, Huang F, Xu X, He H, Zhang Y . High expression of hypoxia inducible factor 1α related with acquired resistant to EGFR tyrosine kinase inhibitors in NSCLC. Sci Rep. 2021; 11(1):1199. PMC: 7806909. DOI: 10.1038/s41598-020-79801-1. View

van der Horst A, Tertoolen L, de Vries-Smits L, Frye R, Medema R, Burgering B . FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279(28):28873-9. DOI: 10.1074/jbc.M401138200. View

Hapke R, Haake S . Hypoxia-induced epithelial to mesenchymal transition in cancer. Cancer Lett. 2020; 487:10-20. PMC: 7336507. DOI: 10.1016/j.canlet.2020.05.012. View

Buler M, Andersson U, Hakkola J . Who watches the watchmen? Regulation of the expression and activity of sirtuins. FASEB J. 2016; 30(12):3942-3960. DOI: 10.1096/fj.201600410RR. View

10.

Nilsson M, Robichaux J, Herynk M, Cascone T, Le X, Elamin Y . Altered Regulation of HIF-1α in Naive- and Drug-Resistant EGFR-Mutant NSCLC: Implications for a Vascular Endothelial Growth Factor-Dependent Phenotype. J Thorac Oncol. 2020; 16(3):439-451. PMC: 8207565. DOI: 10.1016/j.jtho.2020.11.022. View

11.

Tan Z, Luo X, Xiao L, Tang M, Bode A, Dong Z . The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications. Mol Cancer Ther. 2016; 15(5):774-82. DOI: 10.1158/1535-7163.MCT-15-0621. View

12.

Keith B, Simon M . Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007; 129(3):465-72. PMC: 3150586. DOI: 10.1016/j.cell.2007.04.019. View

13.

Chen H, Zhang W, Cheng X, Guo L, Xie S, Ma Y . β2-AR activation induces chemoresistance by modulating p53 acetylation through upregulating Sirt1 in cervical cancer cells. Cancer Sci. 2017; 108(7):1310-1317. PMC: 5497720. DOI: 10.1111/cas.13275. View

14.

Roth K, Mambetsariev I, Kulkarni P, Salgia R . The Mitochondrion as an Emerging Therapeutic Target in Cancer. Trends Mol Med. 2019; 26(1):119-134. PMC: 6938552. DOI: 10.1016/j.molmed.2019.06.009. View

15.

Abdel-Wahab A, Mahmoud W, Al-Harizy R . Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res. 2019; 150:104511. DOI: 10.1016/j.phrs.2019.104511. View

16.

Okamoto K, Saito Y, Narumi K, Furugen A, Iseki K, Kobayashi M . Different mechanisms of cisplatin resistance development in human lung cancer cells. Biochem Biophys Res Commun. 2020; 530(4):745-750. DOI: 10.1016/j.bbrc.2020.07.040. View

17.

Cruz-Bermudez A, Vicente-Blanco R, Laza-Briviesca R, Garcia-Grande A, Laine-Menendez S, Gutierrez L . PGC-1alpha levels correlate with survival in patients with stage III NSCLC and may define a new biomarker to metabolism-targeted therapy. Sci Rep. 2017; 7(1):16661. PMC: 5709355. DOI: 10.1038/s41598-017-17009-6. View

18.

You J, Cheng J, Yu B, Duan C, Peng J . Baicalin, a Chinese Herbal Medicine, Inhibits the Proliferation and Migration of Human Non-Small Cell Lung Carcinoma (NSCLC) Cells, A549 and H1299, by Activating the SIRT1/AMPK Signaling Pathway. Med Sci Monit. 2018; 24:2126-2133. PMC: 5909419. DOI: 10.12659/msm.909627. View

19.

Matsuo N, Azuma K, Sakai K, Hattori S, Kawahara A, Ishii H . Association of EGFR Exon 19 Deletion and EGFR-TKI Treatment Duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients. Sci Rep. 2016; 6:36458. PMC: 5095551. DOI: 10.1038/srep36458. View

20.

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View