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
Affiliations
Yuanyuan Bai
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Yiqing You
Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
Daoxun Chen
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Yongmei Chen
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Zhenjie Yin
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Shangfan Liao
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Bingyong You
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Dongming Lu
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China
Yingming Sun
Department of Oncology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China; Corresponding author
Lixian Wu
Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, China; Corresponding author
Yongyang Wu
Department of Urology, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, Fujian 365100, P.R. China; Corresponding author
Summary: 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.
