Abstract | PURPOSE: MATERIALS AND METHODS: To define the TKI-resistance mechanism and identify new therapeutic target for TKI-resistant ccRCC, an integrative differential gene expression analysis was performed using acquired resistant cohort and a public dataset. Sunitinib-resistant RCC cell lines were established and used to test their malignant behaviors of TKI resistance through in vitro and in vivo studies. Immunohistochemistry was conducted to compare expression between the tumor and normal kidney and verify expression of pathway-related proteins. RESULTS: Integrated differential gene expression analysis revealed increased interferon-induced transmembrane protein 3 (IFITM3) expression in post-TKI samples. IFITM3 expression was increased in ccRCC compared with the normal kidney. TKI-resistant RCC cells showed high expression of IFITM3 compared with TKI-sensitive cells and displayed aggressive biologic features such as higher proliferative ability, clonogenic survival, migration, and invasion while being treated with sunitinib. These aggressive features were suppressed by the inhibition of IFITM3 expression and promoted by IFITM3 overexpression, and these findings were confirmed in a xenograft model. IFITM3-mediated TKI resistance was associated with the activation of TRAF6 and MAPK/AP-1 pathways. CONCLUSIONS: These results demonstrate IFITM3-mediated activation of the TRAF6/MAPK/AP-1 pathways as a mechanism of acquired TKI resistance, and suggest IFITM3 as a new target for TKI-resistant ccRCC.
|
Authors | Se Un Jeong, Ja-Min Park, Sun Young Yoon, Hee Sang Hwang, Heounjeong Go, Dong-Myung Shin, Hyein Ju, Chang Ohk Sung, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho |
Journal | Investigative and clinical urology
(Investig Clin Urol)
Vol. 65
Issue 1
Pg. 84-93
(Jan 2024)
ISSN: 2466-054X [Electronic] Korea (South) |
PMID | 38197755
(Publication Type: Journal Article)
|
Copyright | © The Korean Urological Association. |
Chemical References |
- IFITM3 protein, human
- Membrane Proteins
- RNA-Binding Proteins
- Sunitinib
- TNF Receptor-Associated Factor 6
- Transcription Factor AP-1
- Vascular Endothelial Growth Factor A
- Tyrosine Kinase Inhibitors
|
Topics |
- Humans
- Carcinoma, Renal Cell
(drug therapy)
- Membrane Proteins
(genetics)
- RNA-Binding Proteins
(genetics)
- Sunitinib
(pharmacology)
- TNF Receptor-Associated Factor 6
- Transcription Factor AP-1
- Vascular Endothelial Growth Factor A
- Tyrosine Kinase Inhibitors
(pharmacology)
- Drug Resistance, Neoplasm
|