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

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.

Low-Dose Metformin Treatment Reduces In Vitro Growth of the LL/2 Non-small Cell Lung Cancer Cell Line

“…This is supported by recent in vivo work demonstrating that metformin alone is not sufficient to reduce NSCLC tumor burden [51]. Indeed, metformin was more effective when combined with another treatment modality (i.e., ionizing radiation, chemotherapeutic, or inhibitor) [31,46,52,53]. Future studies should be conducted to further investigate metformin as a co-therapy and approached with more targeted drug delivery tactics.…”

Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis

“…Pioneer genomic studies in HCC patients show by the rst that survival in patients with mutations in the tumor suppressor p53 is diminished 42 . In fact, mutation of TP53 occurs early and it is a driver of HCC progression 43 , whilst the conservation of wild type TP53 could represent a signi cant bene t in the outcome of HCC, and a possibility to stabilize or activate p53 through novel strategies with antitumor results 44,45,46 . Wild type p53 is involved in the negative regulation of different EMT transcription factors in HCC 33,47,48 , hence we postulate that the status of p53 could be a strong determinant of the migratory ability of HCC cells and that the increase of WT p53 could lead to anti migratory effects.…”

Targeting histone demethylases as a potential cancer therapy (Review)

“…Furthermore, it was indicated that KDM5B suppressed BRCA1, caveolin 1 and homeobox A5 expression by reducing H3K4me3 levels and facilitated G1 progression and tumor growth in breast cell lines (126). Through activating the c-Met signaling pathway or inhibiting p53 accumulation, KDM5B promoted lung cancer cell aggressiveness (127,128). In addition, other studies also indicated that knockdown of KDM5B led to cell cycle arrest at the G1/S phase; the ability of KDM5B to influence tumor proliferation by adjusting the cell cycle was identified in liver cancer, bladder cancer and acute lymphoblastic leukemia (129)(130)(131).…”