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首页> 外文期刊>Oncogene >SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy
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SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy

机译：SMAD4 缺失通过促进线粒体自噬限制了胰腺癌细胞对复合物 I 抑制的脆弱性

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Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor beta (TGF beta) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGF beta-treatment and the loss of SMAD4, a downstream member of TGF beta signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGF beta-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGF beta signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGF beta signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.
机译：胰腺癌是最致命的癌症之一，归因于缺乏有效的治疗选择和耐药性。线粒体抑制剂已成为一类很有前途的抗癌药物，几种电子传递链（ETC）抑制剂正在临床评估中。我们假设对双胍类 ETC 抑制剂的耐药性可能是由 SMAD4 失活诱导的，SMAD4 是一种参与转化生长因子 β （TGF β） 信号传导的重要肿瘤抑制因子，并且与线粒体活性改变有关。在这里，我们表明，矛盾的是，TGF β 处理和 SMAD4（TGF β 信号级联的下游成员）的缺失都会诱导对双胍类药物的抵抗，减少线粒体呼吸，并使线粒体网络断裂。从机制上讲，SMAD4 缺陷细胞的耐药性是由 MAPK/ERK 信号驱动的线粒体吞噬通量增加介导的，而 TGF β 诱导的耐药性与自噬无关，并与上皮间充质转化 （EMT） 有关。有趣的是，线粒体靶向他莫昔芬是一种正在临床试验中的复合物 I 抑制剂，它克服了由 SMAD4 缺陷或 TGF β 信号传导介导的耐药性。我们的数据指出了 PDAC 治疗耐药性的差异机制，分别由 TGF β 信号传导和 SMAD4 缺失引起。这些发现将有助于开发以SMAD4作为合理预测标志物的胰腺癌患者的线粒体靶向治疗。

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