The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma.

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-10-30 DOI:10.1038/s41418-024-01407-1

Chang Liu, Cheng Zhang, Hongkun Wu, Zhibin Zhao, Zhenhua Wang, Xiaomin Zhang, Jieli Yang, Wenlong Yu, Zhexiong Lian, Minghui Gao, Lin Zhou

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Abstract

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.

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AKR1C1-CYP1B1-cAMP信号轴控制着肝外胆管癌的致瘤性和易感性。

肝外胆管癌（ECC）是一种恶性程度很高的癌症，发病率不断上升，但由于治疗方法有限，预后较差。基于对 ECC 患者样本的基因组分析，我们在此报告醛酮还原酶家族 1 成员 C1（AKR1C1）在人类 ECC 组织中高表达，并与 ECC 的进展和不良预后密切相关。耐人寻味的是，我们发现诱导性 AKR1C1 敲除会引发 ECC 细胞发生铁变态反应。从机理上讲，AKR1C1 通过泛素-蛋白酶体降解，降低了细胞色素 P450 家族成员 CYP1B1 蛋白的稳定性，而 CYP1B1 是新发现的铁变态反应介质。此外，AKR1C1 还通过芳基烃受体（AHR）转录因子降低 CYP1B1 mRNA 水平。此外，AKR1C1-CYP1B1 轴还能通过 cAMP-PKA 信号通路调节 ECC 细胞中的铁变态反应。最后，在 ECC 的异种移植小鼠模型中，AKR1C1 的缺失会使癌细胞对铁凋亡敏感，并与铁凋亡诱导剂协同抑制肿瘤生长。因此，AKR1C1-CYP1B1-cAMP 信号轴是治疗 ECC 的一个很有前景的治疗靶点，尤其是与铁变态反应诱导剂联合使用时。

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

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.