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.
Abbreviations:
AKI (acute kidney injury), BUN (blood urea nitrogen), CKD (chronic kidney disease), CDKs (cyclin-dependent kinases), CDK4 (cyclin-dependent kinase 4), F2,6P2 (fructose-2,6-bisphosphate), Kim-1 (kidney injury molecule-1), OXPHOS (oxidative phosphorylation), PFK-1 (6-phosphofructo-1-kinase), PFK15 (1-(4pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), p-Rb (phosphorylated Rb), Rb (retinoblastoma tumor suppressor), RPTCs (rat renal proximal tubular cells), SCr (serum creatinine), TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: October 12, 2022
Accepted:
October 6,
2022
Received in revised form:
September 30,
2022
Received:
July 28,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
Published by Elsevier Inc.
