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  • Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells.

Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells.

Aging (2021-09-17)
Tharcisio Citrangulo Tortelli, Rodrigo Esaki Tamura, Mara de Souza Junqueira, Janio da Silva Mororó, Silvina Odete Bustos, Renato Jose Mendonça Natalino, Shonagh Russell, Laurent Désaubry, Bryan Eric Strauss, Roger Chammas
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Metformin hydrochloride, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Thiazolyl Blue Tetrazolium Bromide, 98%
Sigma-Aldrich
Pifithrin-μ, ≥97% (HPLC), solid
Sigma-Aldrich
PBIT, ≥98% (HPLC)
Sigma-Aldrich
SIGMAFAST Protease Inhibitor Cocktail Tablets, EDTA-Free, for use in purification of Histidine-tagged proteins
Sigma-Aldrich
Hoechst 33258 solution, 1 mg/mL in H2O, ≥98.0% (HPLC)