Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2
Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expans...
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Veröffentlicht in: | Scientific reports 2016-04, Vol.6 (1), p.23824-23824, Article 23824 |
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Sprache: | eng |
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Zusammenfassung: | Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expansion of MDSCs in response to chemotherapies is poorly understood. In the present study, we used
in vitro
cell culture and
in vivo
animal studies to demonstrate that doxorubicin-resistant breast cancer cells secret significantly more prostaglandin E
2
(PGE
2
) than their parental doxorubicin-sensitive cells. The secreted PGE
2
can stimulate expansion and polymerization of MDSCs by directly target to its receptors, EP2/EP4, on the surface of MDSCs, which consequently triggers production of miR-10a through activating PKA signaling. More importantly, activated MDSCs can inhibit CD4
+
CD25
−
T cells as evidenced by reduced proliferation and IFN-γ release. In order to determine the molecular pathway that involves miR-10a mediated activation of MDSCs, biochemical and pharmacological studies were carried out. We found that miR-10a can activate AMPK signaling to promote expansion and activation of MDSCs. Thus, these results reveal, for the first time, a novel role of PGE
2
/miR-10a/AMPK signaling axis in chemotherapy-induced immune resistance, which might be targeted for treatment of chemotherapy resistant tumors. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/srep23824 |