AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2024-09-02 DOI:10.1016/j.apsb.2024.08.031

Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi

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引用次数: 0

Abstract

Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both and . Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.

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AKR1C1 与 STAT3 相互作用，增加细胞内谷胱甘肽含量，使结肠直肠癌患者对奥沙利铂产生抗药性

奥沙利铂（OXA）是一种铂类化疗药，目前仍是晚期结直肠癌（CRC）一线治疗的主要药物。然而，OXA 最终产生耐药性是一项重大的临床挑战。在本研究中，我们证明了醛酮还原酶 1C1 (AKR1C1) 在获得 OXA 耐药性后会在 CRC 细胞中过表达，这在 OXA 耐药性 CRC 细胞系中非常明显。我们采用基因沉默和药物抑制策略，证实抑制 AKR1C1 可恢复对 OXA 的敏感性。从机理上讲，AKR1C1 与转录因子 STAT3 相互作用并激活其上调谷氨酸转运体 EAAT3，从而提高细胞内谷胱甘肽水平并赋予 OXA 抗性。金刚烷内酯是一种强效的 AKR1C1 天然产物抑制剂，它能有效逆转这种化疗耐药性，同时限制对 OXA 具有耐药性的 CRC 细胞的生长。我们的研究结果揭示了 OXA 耐药性背后一个关键的 AKR1C1 依赖性机制，并提出了一种很有前景的组合治疗策略来克服 CRC 中的这种耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.