Dapagliflozin induces apoptosis by downregulating cFILPL and increasing cFILPS instability in Caki-1 cells

Ji Hoon Jang; Tae-Jin Lee; Eon-Gi Sung; In-Hwan Song; Joo-Young Kim

doi:10.3892/ol.2022.13521

Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki-1 cells

Oncol Lett. 2022 Sep 22;24(5):401. doi: 10.3892/ol.2022.13521. eCollection 2022 Nov.

Authors

Ji Hoon Jang¹, Tae-Jin Lee¹, Eon-Gi Sung¹, In-Hwan Song¹, Joo-Young Kim¹

Affiliation

¹ Department of Anatomy, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.

Abstract

Dapagliflozin is a sodium/glucose cotransporter 2 inhibitor used recently to treat patients with type 2 diabetes. A recent study has demonstrated that dapagliflozin induces apoptosis in human renal and breast tumor cells. However, to the best of our knowledge, the molecular mechanism underlying dapagliflozin-mediated apoptosis in Caki-1 human renal carcinoma cells has not been elucidated. The present study demonstrated that the dapagliflozin treatment dose-dependently increased cell death in Caki-1 cells. Dapagliflozin treatment also induced apoptosis as confirmed by FITC-conjugated Annexin V/PI staining. Additionally, treatment with dapagliflozin reduced the expression levels of anti-apoptotic proteins, cellular Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein (cFLIP)_L and cFLIP_S in Caki-1 cells. Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone inhibited dapagliflozin-induced apoptosis, implying that dapagliflozin-induced apoptosis is regulated by a caspase-dependent pathway. By contrast, N-acetylcysteine had no effect on dapagliflozin-induced apoptosis and downregulation of cFLIP_L and cFLIP_S expression. Furthermore, overexpression of cFLIP_L, but not cFLIP_S, partially inhibited apoptosis induced by dapagliflozin. cFLIP_L and cFLIP_S mRNA levels remained constant in Caki-1 cells after treatment with 0, 20, 40, 60, 80 and 100 µM dapagliflozin. Notably, it was confirmed that cFLIP_S protein levels were reduced due to the increased cFLIP_S instability in dapagliflozin-treated Caki-1 cells. The present study also demonstrated that dapagliflozin had no effect on HK-2 normal human kidney cells. Taken together, the present study revealed that dapagliflozin induced apoptosis via the downregulation of cFLIP_L and an increase in cFLIP_S instability, suggesting that dapagliflozin may be a feasible drug candidate for the treatment of human renal cancer.

Keywords: apoptosis; cellular Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein; dapagliflozin; renal carcinoma.

Grants and funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant no. 2020R1I1A1A01068857).