University of Pittsburgh Cancer Institute, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
J Biol Chem. 2011 Jun 3;286(22):20087-99. doi: 10.1074/jbc.M110.191718. Epub 2011 Apr 5.
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.
在这里，我们证明了噻唑烷二酮（曲格列酮，Rezulin），一种过氧化物酶体增殖物激活受体激动剂，与表皮生长因子家族成员 10（heregulin，HRG）协同作用，诱导乳腺癌细胞大量死亡。尽管 HRG 与曲格列酮（HRG/TGZ）联合诱导细胞凋亡和坏死，但主要的细胞死亡方式是非胱天蛋白酶依赖性的，并通过坏死发生。这种联合作用增加了线粒体中超氧阴离子的产生，从而破坏了线粒体的潜能。用 N-乙酰-L-半胱氨酸预处理和表达过氧化氢酶可以改善联合处理诱导的细胞死亡，表明氧化应激在介导 HRG/TGZ 诱导的细胞死亡中起作用。值得注意的是，丙酮酸的预处理显著阻止了细胞死亡，这表明代谢应激与 HRG/TGZ 诱导的细胞死亡之间存在潜在的机制联系。激活 HRG 信号轴已被认为是乳腺癌的预后不良因素，并导致对表皮生长因子受体酪氨酸激酶抑制剂（gefitinib，Iressa）和他莫昔芬的耐药性。然而，我们在这里提出的矛盾数据表明，过氧化物酶体增殖物激活受体-γ 配体治疗乳腺癌时，HRG 表达实际上可能是有益的。总之，HRG 与 TGZ 的联合可能为开发治疗凋亡抵抗和/或激素难治性乳腺癌的新策略提供基础。
