Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) frequently recurs or metastasizes after surgical resection. Everolimus, an mTOR inhibitor, is used as a second-line treatment, but the response of RCC to everolimus is insufficient. Metformin is an antidiabetic drug; recent reports have indicated its anti-cancer effects in various cancers, and it is known to have synergistic effects with other drugs. We investigated the possibility of coadministering everolimus and metformin as an effective treatment for RCC. RCC cells treated with a combination of the two drugs showed significantly inhibited cell viability, cell migration, and invasion, and increased apoptosis compared to those treated with each drug alone. An anti-cancer synergistic effect was also confirmed in the xenograft model. Transcriptome analysis for identifying the underlying mechanism of the combined treatment showed the downregulation of mitochondrial fusion genes and upregulation of mitochondrial fission genes by the combination treatment. Changes in mitochondrial dynamics following the combination treatment were observed using LysoTracker, LysoSensor, and JC-1 staining. In conclusion, the combination of everolimus and metformin inhibited RCC growth by disrupting mitochondrial dynamics. Therefore, we suggest that a treatment combining metformin and everolimus disrupts mitochondrial dynamics in RCC, and may be a novel strategy for RCC treatment.

Role of NF-κB pathway in kidney renal clear cell carcinoma and its potential therapeutic implications

“…To further explore the potential value of the NF-κB pathway in the clinical treatment of patients with KIRC, we plotted box plots based on drug susceptibility predictions in the GDSC database to determine the effect of the NF-κB pathway on IC50 of 12 commonly renal carcinoma targeted drugs. In these drugs, sorafenib is the first targeted multi-kinase inhibitor and first-line chemical drug approved for the treatment of RCC, which blocks formation of tumor neovascularization and directly inhibits the proliferation of RCC cells by blocking RAF/MEK/ERK signaling pathway [ 24 ]; Sunitinib inhibits the development of tumor-associated vascular disorders and affects the infiltration of immune cells such as regulatory T cells and macrophages [ 25 ]; metformin inhibits RCC cell viability (including cell migration and invasion) and increases apoptosis by disrupting mitochondrial dynamics [ 26 ]; other drugs also show different mechanisms of action in cancer suppression. We found that sensitivity to sorafenib, gefitinib, and metformin was higher in the downregulated NF-κB group (C3) but not in the upregulated NF-κB group (C2).…”