Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington D.C.
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Res. 2019 Apr;17(4):918-928. doi: 10.1158/1541-7786.MCR-18-0481. Epub 2019 Jan 17.
Approximately 30% of aromatase-inhibitor-resistant, estrogen receptor-positive patients with breast cancer benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy-resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi-mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxy tamoxifen with salubrinal enhanced apoptotic potency. IMPLICATIONS: These results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a drugable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.
大约 30%的芳香酶抑制剂耐药、雌激素受体阳性的乳腺癌患者受益于雌激素治疗。这种神秘的雌激素作用还没有被很好地理解，它是如何发生的仍然难以捉摸。研究表明，未折叠蛋白反应和细胞凋亡途径在介导雌激素触发的细胞凋亡中起着重要作用。使用 MCF7:5C 细胞，该细胞模拟芳香酶抑制剂耐药，并且对雌激素高度敏感，如通过诱导细胞凋亡所证明的，我们将增加的全局蛋白质翻译负荷定义为雌激素诱导细胞凋亡的触发因素。蛋白激酶 RNA 样内质网激酶途径被激活，随后真核起始因子 2α(eIF2α)的磷酸化增加。这些作用阻止了全局蛋白质翻译，但优先允许特定转录因子（如激活转录因子 4 和 C/EBP 同源蛋白）的高表达，从而促进细胞凋亡。值得注意的是，我们通过使用 salubrinal 增加磷酸化 eIF2α 的水平，在另外两种内分泌治疗耐药细胞系（MCF7/LCC9 和 T47D:A18/4-OHT）中重现了 MCF7:5C 的这种表型，salubrinal 是一种药理学上抑制负责 eIF2α 去磷酸化的酶、GADD34 和 CReP 的药物。这些基因的 RNAi 介导的消融诱导了与 salubrinal 处理相同的信号转导的细胞凋亡。此外，将 4-羟基他莫昔芬与 salubrinal 联合使用增强了细胞凋亡的效力。意义：这些结果不仅阐明了雌激素诱导细胞凋亡的机制，而且还确定了一个可治疗的靶标，用于潜在的治疗干预，该靶标可以模拟某些乳腺癌中雌激素的有益作用。
