Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer
Navjotsingh Pabla, Guie Dong, Man Jiang, Shuang Huang, M. Vijay Kumar, Robert O. Messing, Zheng Dong
Navjotsingh Pabla, Guie Dong, Man Jiang, Shuang Huang, M. Vijay Kumar, Robert O. Messing, Zheng Dong
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Research Article Nephrology

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 8

Effect of PKCδ inhibition on cisplatin-induced apoptosis in multiple cancer cell lines.

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Effect of PKCδ inhibition on cisplatin-induced apoptosis in multiple can...
(A) Effect of PKCδ inhibitor δV1-1 on cisplatin-induced apoptosis in cancer cells. Indicated cell lines were pretreated with 2 μM Tat or δV1-1 peptide for 1 hour in reduced serum medium before treating with 25 μM cisplatin for 24 hours, and apoptosis was monitored as described in Methods. Mean ± SD, n = 3. *P < 0.05 versus cisplatin plus Tat group. (B) Effect of genetic inhibition of PKCδ on cisplatin-induced apoptosis. Indicated cell lines were transfected with either empty vector, PKCδ-KD, scrambled siRNA, or PKCδ-siRNA, and 48 hours after transfection, the cells were treated with 20 μM cisplatin for 24 hours, and apoptosis was estimated. Mean ± SD, n = 3. *P < 0.05 versus vector group; #P < 0.05 versus scrambled siRNA group.