The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells.
The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells.
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作者：
Blanco FF;Jimbo M;Wulfkuhle J;Gallagher I;Deng J;Enyenihi L;Meisner-Kober N;Londin E;Rigoutsos I;Sawicki JA;Risbud MV;Witkiewicz AK;McCue PA;Jiang W;Rui H;Yeo CJ;Petricoin E;Winter JM;Brody JR
此前已有研究表明，胰腺导管腺癌 (PDA) 肿瘤表现出高水平缺氧，其特点是低氧分压 (pO2) 和细胞内 O2 灌注减少。慢性缺氧与细胞毒性化疗和放化疗的耐药性密切相关，这种现象被称为缺氧诱导的化疗耐药性，这一现象尚未得到充分研究。缺氧诱导的促癌丝氨酸-苏氨酸激酶 PIM1（莫洛尼鼠白血病病毒 1 的原病毒整合位点）已成为 PDA 和其他癌症中缺氧诱导的化疗耐药性的关键调节因子。尽管之前已经描述了其在治疗抵抗中的作用，但 PIM1 在 PDA 中过度表达背后的分子机制尚不清楚。在这里，我们证明，PIM1 mRNA 3’非翻译区的 38 个碱基对区域内存在的富含 AU 的顺式作用元件 (ARE) 在肿瘤缺氧的情况下介导与 mRNA 稳定因子 HuR（Hu 抗原 R）的调节相互作用。 HuR 主要在 PDA 细胞的细胞核中表达，响应缺氧应激而易位至细胞质并稳定 PIM1 mRNA 转录物，导致 PIM1 蛋白过度表达。反相蛋白阵列显示，HuR 介导的 PIM1 调节通过凋亡效应子 BAD 的磷酸化和失活以及 MEK1/2 的激活来保护细胞免受缺氧应激。重要的是，MS-444 对 HuR 的药理学抑制可抑制 HuR 同二聚化及其细胞质易位，消除缺氧诱导的 PIM1 过度表达，并显着增强生理低氧条件下 PDA 细胞对奥沙利铂和 5-氟尿嘧啶的敏感性。总而言之，这些结果支持这样的观点：HuR 使 PDA 细胞在应激性肿瘤微环境中具有生长优势，从而具有促生存特性。因此，这些研究提供的证据表明，治疗性破坏 HuR 对 PIM1 的调节可能是打破驻留在缺氧 PDA 微环境中的 PDA 细胞获得的难以捉摸的化疗耐药机制的关键策略。
Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3’-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR’s regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.
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