| First Author | Wen L | Year | 2023 |
| Journal | Transl Res | Volume | 253 |
| Pages | 31-40 | PubMed ID | 36243313 |
| Mgi Jnum | J:337212 | Mgi Id | MGI:7493546 |
| Doi | 10.1016/j.trsl.2022.10.001 | Citation | Wen L, et al. (2023) PFKFB3 mediates tubular cell death in cisplatin nephrotoxicity by activating CDK4. Transl Res 253:31-40 |
| abstractText | Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. However, the mechanism of cisplatin nephrotoxicity remains unclear and no effective kidney protective strategies are available. Here, we report the induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in both in vitro cell culture and in vivo mouse models of cisplatin nephrotoxicity. Notably, PFKFB3 was mainly induced in the nucleus of kidney tubular cells, suggesting a novel function other than its canonical role in glycolysis. Both pharmacological inhibition and genetic silencing of PFKFB3 led to the suppression of cisplatin-induced apoptosis in cultured renal proximal tubular cells (RPTCs). Moreover, cisplatin-induced kidney injury or nephrotoxicity was ameliorated in renal proximal tubule-specific PFKFB3 knockout mice. Mechanistically, we demonstrated the interaction of PFKFB3 with cyclin-dependent kinase 4 (CDK4) during cisplatin treatment, resulting in CDK4 activation and consequent phosphorylation and inactivation of retinoblastoma tumor suppressor (Rb). Inhibition of CDK4 reduced cisplatin-induced apoptosis in RPTCs and kidney injury in mice. Collectively, this study unveils a novel pathological role of PFKFB3 in cisplatin nephrotoxicity through the activation of the CDK4/Rb pathway, suggesting a new kidney protective strategy for cancer patients by blocking PFKFB3. |
