Dapagliflozin induces apoptosis by downregulating cFIL[P.sub.L] and increasing cFIL[P.sub.s] instability in Caki-1 cells

• Published in: Oncology letters 2022-11, Vol.24 (5), p.1
• Main Authors: Jang, Ji Hoon, Lee, Tae-Jin, Sung, Eon-Gi, Song, In-Hwan, Kim, Joo-Young
• Format: Article
• Language: English
• Subjects: Apoptosis; Dapagliflozin; Enzymes; RNA; Type 2 diabetes
• ISSN: 1792-1074
• DOI: 10.3892/ol.2022.13521

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).sub.L] and cFLI[P.sub.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 down-regulation of cFLI[P.sub.L] and cFLI[P.sub.S] expression. Furthermore, overexpression of cFLI[P.sub.L], but not cFLI[P.sub.S], partially inhibited apoptosis induced by dapagliflozin. cFLI[P.sub.L] and cFLI[P.sub.S] mRNA levels remained constant in Caki-1 cells after treatment with 0, 20, 40, 60, 80 and 100 [MICRO]M dapagliflozin. Notably, it was confirmed that cFLI[P.sub.S] protein levels were reduced due to the increased cFLI[P.sub.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 cFLI[P.sub.L] and an increase in cFLI[P.sub.S] instability, suggesting that dapagliflozin may be a feasible drug candidate for the treatment of human renal cancer.