title: Synergistic interactions between heregulin and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist in breast cancer cells.
abstract: Here, we demonstrate that troglitazone (Rezulin), a peroxisome proliferator-activated receptor agonist, acted in synergy with heregulin to induce massive cell death in breast cancer cells. Although the combination of heregulin and troglitazone (HRG/TGZ) induced both apoptosis and necrosis, the main mode of cell death was caspase-independent and occurred via necrosis. This combination increased generation of superoxide in mitochondria, which in turn destabilized mitochondria potential. Pretreatment with N-acetyl-l-cysteine and catalase expression ameliorated cell death induced by the combination treatment, indicating a role of oxidative stress in mediating HRG/TGZ-induced cell death. Notably, pretreatment with pyruvate significantly prevented the cell death, suggesting a potential mechanistic link between metabolic stress and HRG/TGZ-induced cell death. The activation of the HRG signaling axis has been considered as a poor prognostic factor in breast cancer and confers resistance to gefitinib (Iressa) and tamoxifen. However, our data presented here paradoxically suggest that HRG expression can actually be beneficial when it comes to treating breast cancer with peroxisome proliferator-activated receptor-γ ligands. Taken together, the combination of HRG and TGZ may provide a basis for the development of a novel strategy in the treatment of apoptosis-resistant and/or hormone-refractory breast cancer.
authors.affiliation: University of Pittsburgh Cancer Institute, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Bae-Hang
authors.initials: BH
authors.lastname: Park
authors.forename: Sean-Bong
authors.initials: SB
authors.lastname: Lee
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
authors.forename: Byeong-Chel
authors.initials: BC
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000819:agonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002839:Chromans / Q000819:agonists / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D009336:Necrosis; D020890:Neuregulin-1 / Q000819:agonists / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000819:agonists / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D020890:Neuregulin-1; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077288:Troglitazone