Phosphorylation and Stabilization of Topoisomerase IIα Protein by p38γ Mitogen-activated Protein Kinase Sensitize Breast Cancer Cells to Its Poisons

Cancer drugs suppress tumor cell growth by inhibiting specific cellular targets. However, most drugs also activate several cellular nonspecific stress pathways, and the implications of these off-target effects are mostly unknown. Here, we report that p38 gamma, but not p38 alpha, MAPK is specifically activated by treatment of breast cancer cells with topoisomerase II (Topo II) drugs, whereas paclitaxel (Taxol) does not have this effect. The activated p38 gamma in turn phosphorylates and stabilizes Topo II alpha protein, and this enhances the growth inhibition by Topo II drugs. Moreover, p38 gamma activity was shown to be necessary and sufficient for Topo II alpha expression, the drug-p38 gamma-Topo II alpha axis is only detected in intrinsically sensitive but not resistant cells, and p38 gamma is co-overexpressed with Topo II alpha protein in primary breast cancers. These results reveal a new paradigm in which p38 gamma actively regulates the drug-Topo II alpha signal transduction, and this may be exploited to increase the therapeutic activity of Topo II drugs.