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首页> 外文期刊>Molecular and Cellular Biology >Downregulation of PHLPP Expression Contributes to Hypoxia-Induced Resistance to Chemotherapy in Colon Cancer Cells
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Downregulation of PHLPP Expression Contributes to Hypoxia-Induced Resistance to Chemotherapy in Colon Cancer Cells

机译：PHLPP表达的下调有助于低氧诱导的结肠癌细胞对化疗的耐药性。

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Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor in colon cancers. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia/anoxia in colon cancer cells. Interestingly, a hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1α but not HIF2α. Whereas the mRNA levels of PHLPP are not significantly altered by oxygen deprivation, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated mTOR activity and protein synthesis. Moreover, oxygen deprivation destabilizes PHLPP protein by decreasing the expression of USP46, a deubiquitinase of PHLPP. Functionally, downregulation of PHLPP contributes to hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understanding of chemoresistance in cancer treatment.
机译：缺氧是实体瘤的特征。大多数肿瘤至少部分缺氧。这种低氧环境在增强抗癌药耐药性中起着关键作用。 PHLPP是Ser / Thr蛋白磷酸酶的新家族，在结肠癌中起着抑癌作用。在这里，我们表明两种PHLPP亚型的表达都受到结肠癌细胞中缺氧/缺氧的负调控。有趣的是，通过敲低HIF1α而不是HIF2α可以减轻低氧诱导的PHLPP表达的降低。尽管PHLPP的mRNA水平没有因氧剥夺而明显改变，但PHLPP表达的降低是由于mTOR下游的蛋白质翻译减少和降解增加所致。具体而言，由于mTOR活性和蛋白质合成的提高，在TSC2或4E-BP1敲低的细胞中部分挽救了低氧诱导的PHLPP的下调。此外，氧剥夺通过降低USP46（一种PHLPP的泛素化酶）的表达来使PHLPP蛋白质不稳定。在功能上，PHLPP的下调有助于结肠癌细胞低氧诱导的化学抗性。两者合计，我们已经确定缺氧是结肠癌中下调PHLPP的一种新机制，并且PHLPP的表达可以作为生物标记，以更好地理解癌症治疗中的化学抗性。

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