Bär Séverine, Rommelaere Jean, Nüesch Jürg P F
Infection and Cancer Program, Tumor Virology Division (F010), German Cancer Research Center (DKFZ), Heidelberg, Germany.
PLoS Pathog. 2015 Mar 5;11(3):e1004703. doi: 10.1371/journal.ppat.1004703. eCollection 2015 Mar.
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.
啮齿动物细小病毒（PVs）的内在亲肿瘤性和抑癌活性为癌症病毒疗法开辟了新前景。病毒增殖、细胞溶解活性和传播与PDK1信号级联的激活紧密相关，该信号级联延迟应激诱导的细胞死亡，并通过PKC（η）驱动的修饰维持细小病毒蛋白NS1的功能。在这里，我们揭示了一种新的PV诱导的细胞内反馈机制，即PKCη/Rdx磷酸化小鼠PDK1:S138并独立于PI3激酶信号激活它。相应的人类PDK1磷酸化S135表现为高度侵袭性脑肿瘤的一个标志，可能有助于H-1PV对人类胶质瘤的高效靶向作用。引人注目的是，尽管H-1PV在正常人类细胞中不会触发PDK1激活，但当表达模拟PDK1磷酸化S135的组成型活性PDK1时，这些细胞会显示出增强的病毒DNA扩增和NS1诱导的死亡。因此，这种修饰似乎是人类胶质瘤恶性进展和对H-1PV诱导的肿瘤细胞杀伤敏感性的一个标志。
