Abstract
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.
Highlights
Protoparvoviruses (PVs) are non-enveloped icosahedral particles 24 nm in diameter, with a 5.1 kb linear single-stranded DNA genome encoding two capsid (VP) and several nonstructural (NS) proteins
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
H-1PV does not promote it in normal human cells, experimentally administered activated phosphoinositide-dependent kinase 1 (PDK1)
Summary
Protoparvoviruses (PVs) are non-enveloped icosahedral particles 24 nm in diameter, with a 5.1 kb linear single-stranded DNA genome encoding two capsid (VP) and several nonstructural (NS) proteins. NS1, the major protoparvoviral regulatory protein, is required for multiple steps in the virus life cycle, ranging from viral DNA amplification and trans-regulation of viral and cellular transcription to the egress and spread of progeny particles [3] Because it interferes with multiple cellular pathways, NS1 appears as the main cytotoxic agent responsible for the oncolytic activity of PVs [4,5]. To ensure virus propagation and spread, the PV minute virus of mice (MVM) has evolved a mechanism for stimulating PDK1 and the downstream kinase PKCη in permissive host cells This activation of PDK1 is associated with its PV-induced trans-phosphorylation by (an) unidentified kinase(s) [8]
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