Glutathione S-transferases P1-mediated interleukin-6 in tumor-associated macrophages augments drug-resistance in MCF-7 breast cancer

Glutathione S-transferase P1 (GSTP1), a phase II detoxifying enzyme, is overexpressed and plays an important role during breast cancer drug resistance. Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, are involved in cancer cell resistance to chemotherapy. Although GSTP1 exists in TAMs, whether GSTP1 in TAMs promotes drug resistance is still unclear. In the current study, we found a novel mechanism that GSTP1 in TAMs contributes breast cancer cell drug resistance. GSTP1 is aberrantly expressed in TAMs from breast cancer tissues of patients after chemotherapy than that without chemotherapy. Adriamycin (ADR) time-dependently induced the expression of GSTP1 in TAMs in vitro. Conditional medium of TAMs significantly inhibited ADR-induced cell death of MCF-7 breast cancer cells. Meanwhile, overexpression of GSTP1 in TAMs promoted the expression and release of interleukin-6 (IL-6) associated with reduced ADR-induced breast cell death, which was reversed by IL-6 antibody. Mechanistically, GSTP1 interacted with inhibitor of nuclear factor κB kinase β (IKKβ) to activate nuclear factor-κB (NF-κB) to induced the expression and release of IL-6 in TAMs. Moreover, IL-6 further upregulated GSTP1 through c-Jun, and ultimately mediated drug resistance in MCF-7 cells. Taken together, our data demonstrated for the first time that GSTP1 in TAMs promoted ADR-resistance in breast cancer by regulating interleukin-6 release.