PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis

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The H-1 protoparvovirus (H-1PV) is the first replication-competent member of the Parvoviridae family to undergo a phase I/IIa clinical trial in patients suffering from glioblastoma multiforme. Although the intrinsic oncotropism and oncolytic activity of protoparvoviruses are well known, the underlying molecular mechanisms remain elusive. Here we identify a PV-induced intracellular loop-back mechanism that promotes PV replication and cytotoxicity through PI3-kinase-independent stimulation of PDK1 and of the PKC and PKB/Akt1 downstream kinases. This mechanism involves PKCη/Rdx-mediated phosphorylation of PDK1 (at S138 in mouse or S135 in human). Interestingly, this phosphorylation appears as a hallmark of highly aggressive brain tumors. Although H-1PV does not promote it in normal human cells, experimentally administered activated PDK1 variants were able to sensitize these cells to virus infection. These data lead us to propose PDK1phosphoS135 as a new candidate marker for monitoring tumor progression and responsiveness to oncolytic parvovirotherapy, particularly in the case of highly aggressive brain tumors. Furthermore, the sensitivity of PDK1phosphoS135-positive cell lines to inhibitors of PKCη/Rdx argues for considering this complex as a potential target for anticancer drug development.

Vyšlo v časopise: PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004703
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004703

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