PKCη/Rdx-driven phosphorylation of PDK1: a novel mechanism promoting cancer cell survival and permissiveness for parvovirus-induced lysis.
The intrinsic oncotropism and oncosuppressive activities of rodent protoparvoviruses (PVs) are opening new prospects for cancer virotherapy. Virus propagation, cytolytic activity, and spread are tightly connected to activation of the PDK1 signaling cascade, which delays stress-induced cell death and sustains functioning of the parvoviral protein NS1 through PKC(η)-driven modifications. Here we reveal a new PV-induced intracellular loop-back mechanism whereby PKCη/Rdx phosphorylates mouse PDK1:S138 and activates it independently of PI3-kinase signaling. The corresponding human PDK1phosphoS135 appears as a hallmark of highly aggressive brain tumors and may contribute to the very effective targeting of human gliomas by H-1PV. Strikingly, although H-1PV does not trigger PDK1 activation in normal human cells, such cells show enhanced viral DNA amplification and NS1-induced death upon expression of a constitutively active PDK1 mimicking PDK1phosphoS135. This modification thus appears as a marker of human glioma malignant progression and sensitivity to H-1PV-induced tumor cell killing.
Infection and Cancer Program, Tumor Virology Division (F010), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Séverine
S
Bär
Infection and Cancer Program, Tumor Virology Division (F010), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jean
J
Rommelaere
Infection and Cancer Program, Tumor Virology Division (F010), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jürg P F
JP
Nüesch
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000628:therapy / Q000821:virology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005910:Glioma / Q000628:therapy / Q000821:virology; D052661:H-1 parvovirus; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D050130:Oncolytic Virotherapy / Q000379:methods*; D010322:Parvoviridae Infections / Q000821:virology*; D017992:Parvovirus; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014162:Transfection
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C071776:radixin; C081975:protein kinase C eta; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C