Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells.

IF 4.6 Q1 ONCOLOGY 癌症耐药(英文) Pub Date : 2023-01-01 DOI:10.20517/cdr.2023.14
Jiuhui Wang, Daotai Nie
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Abstract

Aim: The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance. Methods: Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance. Results: PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors. Conclusion: PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.

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孕激素X受体与缺氧诱导因子-1的相互作用调控前列腺癌细胞的化疗耐药。
目的:核孕激素X受体(nuclear pregnane X receptor, PXR)是类固醇和外源药物代谢的关键调节因子,在形成肿瘤细胞对化疗的反应中起重要作用。肿瘤组织缺氧具有多方面的影响,包括多重耐药。本研究的目的是确定PXR是否与缺氧诱导的耐药有关。方法:采用转移性前列腺癌细胞,研究PXR与缺氧诱导因子-1 (HIF-1)在缺氧相关耐药中的相互作用。通过检测PXR和HIF-1的报告基因或靶基因的表达来测定其活性。采用共免疫沉淀法(Co-IP)测定PXR与HIF-1的相互作用。消融或抑制PXR或HIF-1被用来确定它们在缺氧诱导的化疗耐药中的作用。结果:PXR被缺氧激活,导致多药耐药蛋白1 (MDR1)表达增加。药理化合物抑制PXR或shRNAs耗竭可降低MDR1的缺氧诱导,使前列腺癌细胞对缺氧下的化疗敏感。缺氧条件下PXR的激活需要HIF-1。共免疫沉淀结果显示HIF-1和PXR可以相互作用,导致这两个转录因子之间的串扰。结论:PXR通过与HIF-1的相互作用参与缺氧诱导的前列腺癌细胞耐药。
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