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

Seong Hwi Hong, Kwang Suk Lee, Hyun Ji Hwang, Sung Yul Park, Woong Kyu Han, Young Eun Yoon

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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.

Original languageEnglish
Article number1211
Issue number7
Publication statusPublished - 2022 Jul

Bibliographical note

Funding Information:
Funding: This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (grant numbers 2018R1D1A-1B07051225 and 2021R1F1A1064309) and the Ministry of Science and ICT (2019M3E5D1A01069349).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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