Wang Jiuhui, Nie Daotai
Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Cancer Drug Resist. 2023 Jun 16;6(2):378-389. doi: 10.20517/cdr.2023.14. eCollection 2023.
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. 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. 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. PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.
核孕烷X受体（PXR）是类固醇和外源性物质代谢的关键调节因子，在塑造肿瘤细胞对化疗的反应中起重要作用。肿瘤组织内的缺氧具有多方面的影响，包括多药耐药性。本研究的目的是确定PXR是否促成缺氧诱导的耐药性。使用转移性前列腺癌细胞研究PXR与缺氧诱导因子-1（HIF-1）在与缺氧相关的耐药性中的相互作用。通过其报告基因或靶基因表达测定来确定PXR和HIF-1的活性。采用免疫共沉淀（Co-IP）法确定PXR与HIF-1的相互作用。通过敲除或抑制PXR或HIF-1来确定它们在缺氧诱导的化疗耐药性中的作用。缺氧激活PXR，导致多药耐药蛋白1（MDR1）表达增加。用药物化合物抑制PXR或用短发夹RNA（shRNA）使其缺失可降低缺氧诱导的MDR1表达，并使前列腺癌细胞在缺氧条件下对化疗敏感。缺氧条件下PXR激活需要HIF-1。免疫共沉淀结果表明，HIF-1与PXR可相互直接作用，导致这两种转录因子之间产生相互影响。PXR通过与HIF-1相互作用促成前列腺癌细胞缺氧诱导的耐药性。
