Research Paper Volume 13, Issue 18 pp 21914—21940
Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells
- 1 Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, SP 01246-000, Brazil
- 2 Laboratory of Cancer Molecular Biology, Federal University of São Paulo, São Paulo, SP 04039-002, Brazil
- 3 Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- 4 Laboratory of Regenerative Nanomedicine (RNM), INSERM U 1260, University of Strasbourg, CRBS, Strasbourg 67000, France
Received: June 16, 2020 Accepted: August 25, 2021 Published: September 16, 2021
https://doi.org/10.18632/aging.203528How to Cite
Copyright: © 2021 Tortelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.
Abbreviations
A549Res: A549 cisplatin resistant cells; AMPK: AMP-activated protein kinase; CIS: Cisplatin; ECAR: Extracellular Acidification Rate; ECH1: Enoyl-CoA Hydratase 1; ETFA: Electron Transfer Flavoprotein Subunit Alpha; FBS: Fetal Bovine Serum; HADHA: Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Alpha; Jarid1b: Jumonji/ARID1 H3K4 Histone Demethylase; LDHB: Lactate Dehydrogenase B; Met: Metformin; MOI: Multiplicity of Infection; NSCLC: Non-Small-Cell Lung Cancer; OCR: Oxygen Consumption Rate; Oct4: Octamer-Binding Transcription Factor 4; OXPHOS: Oxidative Phosphorylation; PGC-1alpha: Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 alpha; ROS: Reactive Oxygen Species; STR: Short Tandem Repeat; SUCLG2: Succinate-CoA Ligase GDP-Forming Subunit Beta; TCGA: The Cancer Genome Atlas.