Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2709-2722. https://doi.org/10.1172/JCI45586.
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Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

Abstract

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.

Authors

Navjotsingh Pabla, Guie Dong, Man Jiang, Shuang Huang, M. Vijay Kumar, Robert O. Messing, Zheng Dong

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Figure 2

The role of Src in cisplatin-induced PKCδ activation.

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The role of Src in cisplatin-induced PKCδ activation. RPTCs were treated...
RPTCs were treated with 20 μM cisplatin for 4 hours in the absence or presence of 20 μM Src inhibitors, PP1 and PP2, or the control compound PP3. (A) Inhibition of PKCδ (tyr-311) phosphorylation during cisplatin treatment by Src inhibitors. Whole cell lysates were collected for immunoblotting of phosphorylated (tyr-311) PKCδ and total PKCδ. (B) Inhibition of PKCδ activity during cisplatin treatment by Src inhibitors. Whole cell lysates were collected for PKCδ immunoprecipitation and in vitro kinase assay. Mean ± SD, n = 4. *P < 0.001 versus control; #P < 0.001 versus cisplatin-only group. (C) Coimmunoprecipitation of Src and PKCδ. Whole cell lysates were collected for immunoprecipitation of PKCδ. The immunoprecipitates were analyzed for the presence of Src and PKCδ by immunoblotting. (D) Coimmunoprecipitation of Src and PKCδ during cisplatin nephrotoxicity in vivo. C57BL/6 mice were injected with 30 mg/kg cisplatin before collection of renal tissues at days 0 and 3. The tissue lysates were immunoprecipitated using an anti-PKCδ antibody, and the immunoprecipitates were examined for Src and PKCδ by immunoblotting.