Amiloride reduces fructosamine-3-kinase expression to restore sunitinib sensitivity in renal cell carcinoma

Yuanyuan Bai; Yiqing You; Daoxun Chen; Yongmei Chen; Zhenjie Yin; Shangfan Liao; Bingyong You; Dongming Lu; Yingming Sun; Lixian Wu; Yongyang Wu

doi:10.1016/j.isci.2024.109997

Amiloride reduces fructosamine-3-kinase expression to restore sunitinib sensitivity in renal cell carcinoma

iScience. 2024 May 16;27(6):109997. doi: 10.1016/j.isci.2024.109997. eCollection 2024 Jun 21.

Authors

Yuanyuan Bai¹, Yiqing You², Daoxun Chen¹, Yongmei Chen¹, Zhenjie Yin¹, Shangfan Liao¹, Bingyong You¹, Dongming Lu¹, Yingming Sun³, Lixian Wu^{4

5}, Yongyang Wu¹

Affiliations

¹ Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China.
² Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
³ Department of Oncology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China.
⁴ Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China.
⁵ Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China.

Abstract

The kidney is a vital organ responsible for water and sodium metabolism, while the primary function of amiloride is to promote the excretion of water and sodium. We investigated amiloride enhanced the sunitinib sensitivity in RCC. We found both sunitinib and amiloride displayed cytotoxicity and exerted the synergy effect in RCC cells in vivo and in vitro arrays. Protein expression profiles were screened via MS/TMT, revealing that FN3K was upregulated in the sunitinib group, and rescued in amiloride and the combination administration. Exogenous FN3K could promote proliferation, invasion and metastasis and decrease the sensitivity of Caki-1 cells to sunitinib, also, exogenous FN3K up-regulated VEGFR2 expression and activated AKT/mTOR signal pathway. More FN3K and VEGFR2 accumulated in R-Caki-1 cells and rescued by amiloride treatment. Co-IP and IF confirmed the interaction between FN3K and VEGFR2. In conclusion, FN3K depletion mediated VEGFR2 disruption promotes amiloride synergized the anti-RCC activity of sunitinib.

Keywords: Cancer; Cell biology; Molecular biology; Proteomics.