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Targeting PP2A inhibits the growth of triple-negative breast cancer cells

机译：靶向PP2A抑制三阴性乳腺癌细胞的生长

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摘要

Triple-negative breast cancer (TNBC) does not respond to widely used targeted/endocrine therapies because of the absence of progesterone and estrogen receptors and HER2 amplification. It has been shown that the majority of TNBC cells are highly sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, but the development of TRAIL resistance limits its efficacy. We previously found that protein phosphatase 2A (PP2A) plays an important role in TRAIL resistance. In this study, we evaluated the effects of PP2A inhibition on cell death in TRAIL-resistant TNBC cells. We found that the PP2A inhibitor LB-100 effectively inhibits the growth of a panel of TNBC cell lines including lines that are intrinsically resistant to TRAIL. Using two TRAIL-resistant cell lines generated from TRAIL-sensitive parental cells (MDA231 and SUM159), we found that both TRAIL-sensitive and -resistant cell lines are equally sensitive to LB-100. We also found that LB-100 sensitizes TNBC cells to clinically used chemotherapeutical agents, including paclitaxel and cisplatin. Importantly, we found that LB-100 effectively inhibits the growth of MDA468 tumors in mice in vivo without apparent toxicity. Collectively, these data suggest that pharmacological inhibition of PP2A activity could be a novel therapeutic strategy for treating patients with TNBC in a clinical setting.
机译：由于不存在黄体酮和雌激素受体和HER2扩增，三重阴性乳腺癌（TNBC）不会响应广泛使用的靶标/内分泌疗法。已经表明，大多数TNBC细胞对肿瘤坏死因子相关的凋亡诱导配体（TRAIL）诱导的细胞凋亡，但迹线阻力的发展限制了其功效。我们以前发现蛋白质磷酸酶2a（pp2a）在耐足迹中起重要作用。在这项研究中，我们评估了PP2A抑制对耐足迹TNBC细胞中细胞死亡的影响。我们发现PP2A抑制剂LB-100有效地抑制了TNBC细胞系的小组的生长，包括本质上耐足迹的线。使用从敏感的父母细胞（MDA231和SUM159）产生的两个抗抗性细胞系，我们发现两条尾随敏感和易感细胞系对LB-100同等敏感。我们还发现，LB-100将TNBC细胞敏化至临床使用的化学蛋白剂，包括紫杉醇和顺铂。重要的是，我们发现LB-100有效地抑制了体内小鼠中MDA468肿瘤的生长而不表达毒性。总的来说，这些数据表明PP2A活性的药理抑制可以是用于治疗临床环境中TNBC患者的新疗效策略。

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