Abstract
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 p38γ, but not p38α, 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 p38γ in turn phosphorylates and stabilizes Topo IIα protein, and this enhances the growth inhibition by Topo II drugs. Moreover, p38γ activity was shown to be necessary and sufficient for Topo IIα expression, the drug-p38γ-Topo IIα axis is only detected in intrinsically sensitive but not resistant cells, and p38γ is co-overexpressed with Topo IIα protein in primary breast cancers. These results reveal a new paradigm in which p38γ actively regulates the drug-Topo IIα signal transduction, and this may be exploited to increase the therapeutic activity of Topo II drugs.
Highlights
Cancer drugs suppress tumor cell growth by inhibiting specific cellular targets
Increased topoisomerase II (Topo II) Drug Sensitivity Correlates with Sustained Levels of Topo II␣—To search for a signaling pathway involved in the activity of Topo II drugs, a group of human breast cancer cell lines were treated with two clinically used Topo II drugs, VP16 and AMSA, and cell growth was assessed by colony formation compared with paclitaxel (Taxol), an important cancer drug that does not inhibit Topo II␣
To determine which of these two p38 proteins is responsive to Topo II drugs, total phosphorylated p38 (p-p38) proteins were isolated with a p-p38 specific antibody, and resulting precipitates were examined by Western blotting using p38␣ and p38␥ isoform-specific antibodies
Summary
Cancer drugs suppress tumor cell growth by inhibiting specific cellular targets. most drugs activate several cellular nonspecific stress pathways, and the implications of these off-target effects are mostly unknown. Increased Topo II Drug Sensitivity Correlates with Sustained Levels of Topo II␣—To search for a signaling pathway involved in the activity of Topo II drugs, a group of human breast cancer cell lines were treated with two clinically used Topo II drugs, VP16 (etoposide) and AMSA (amsacrine), and cell growth was assessed by colony formation compared with paclitaxel (Taxol), an important cancer drug that does not inhibit Topo II␣.
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