title: 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.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, USA.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.forename: Guie
authors.initials: G
authors.lastname: Dong
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: M Vijay
authors.initials: MV
authors.lastname: Kumar
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; C085746:rottlerin; D019061:src-Family Kinases; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin