Autocrine Growth Hormone-Triggered Curcumin Resistance Abolished by NF-?oB Signaling Pathway Dependent on Inflammatory Cytokines and Active Polyamine Catabolic Machinery in MCF-7, MDA-MB-453 and MDA-MB-231 Breast Cancer Cells

摘要

Autocrine Growth Hormone (GH) induces cell growth, proliferation metastasis in breast cancer. Curcumin is a promising therapeutic agent in cancer through affecting different molecular targets. Our aim was to demonstrate the molecular machinery of curcumin-mediated apoptosis in autocrine GH + MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells (BCCs). Stable GH expressing BCCs were generated by GH gene insert PC3.1 plasmid transfection and Neomycin selection. Although GH + cells are resistant to curcumin treatment, dose-dependent drug exposure decreased cell viability, inhibited colony formation, invasion-metastasis via suppressing GH expression in each BCCs. Anti-hormonal concentration of curcumin (20 ?μM for MCF-7, MDA-MB-453 and 25 ?μM for MDA-MB-231) inhibited NF-?oB p65 (Ser 536) phosphorylation and decreased DNA binding activity of NF-?oB p65 in autocrine GH expressing BCCs. In addition, autocrine GH-mediated IL-1?±, IL-6, IL-1?2 pro-inflammatory cytokine expressions downregulated by curcumin treatment. Moreover, curcumin overcome autocrine GH triggered drug resistant and induced caspase-mediated apoptotic cell death through activating Polyamine (PA) catabolic pathway enzymes which led to generation of toxic by-products such as H2O2 in MCF-7, MDA-MB-453 and MDA-MB-231 GH + BCCs. In conclusion, curcumin could overcome GH-mediated resistant phenotype via modulating NF-?oB-mediated inflammatory cytokine expression and PA catabolic machinery activation in breast cancer cells.