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p34SEI-1 Inhibits Doxorubicin-Induced Senescence through a Pathway Mediated by Protein Kinase C-δ and c-Jun-NH2-Kinase 1 Activation in Human Breast Cancer MCF7 Cells

In this study, we describe a novel function of the p34SEI-1 protein, which is both an oncogenic protein and a positive regulator of the cell cycle. The p34SEI-1 protein was found to inhibit doxorubicin-induced senescence. We investigated the molecular mechanisms of the inhibitory effect of p34SEI-1 on senescence. First, we found that the activation of protein kinase C-δ (PKC-δ), which is cleaved into a 38 kDa active form from a 78 kDa pro-form, induced after doxorubicin treatment, was inhibited by p34SEI-1. Furthermore, p34SEI-1 induced the ubiquitination of PKC-δ. Yet, there is no interaction between p34SEI-1 and PKC-δ. We also found that the phosphorylation of c-Jun-NH2-kinase 1 (JNK1) induced after doxorubicin treatment was suppressed by p34SEI-1, but not in JNK2. Consistently, pharmacologic or genetic inactivation of either PKC-δ or JNK1 was found to inhibit doxorubicin-induced senescence. In addition, the genetic inactivation of PKC-δ by PKC-δ small interfering RNA resulted in an inhibition of JNK1 activation, but PKC-δ expression was not inactivated by JNK1 small interfering RNA, implying that the activation of JNK1 could be dependently induced by PKC-δ. Therefore, p34SEI-1 inhibits senescence by inducing PKC-δ ubiquitination and preventing PKC-δ–dependent phosphorylation of JNK1. [Mol Cancer Res 2009;7(11):1845–53]