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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 
 GENES, Vol.13(7) : 1211, 2022-07 
Journal Title
Issue Date
Carcinoma, Renal Cell* / drug therapy ; Carcinoma, Renal Cell* / genetics ; Carcinoma, Renal Cell* / pathology ; Cell Line, Tumor ; Cell Proliferation ; Everolimus / pharmacology ; Everolimus / therapeutic use ; Humans ; Kidney Neoplasms* / drug therapy ; Kidney Neoplasms* / genetics ; Kidney Neoplasms* / pathology ; Metformin* / pharmacology ; Mitochondrial Dynamics ; Neoplasm Recurrence, Local
everolimus ; metformin ; mitochondrial dynamics ; renal cell carcinoma
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.
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1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Lee, Kwang Suk(이광석) ORCID logo https://orcid.org/0000-0002-7961-8393
Han, Woong Kyu(한웅규) ORCID logo https://orcid.org/0000-0002-2527-4046
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