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

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

  • Cell Death Differ. 2024 Oct 30. doi: 10.1038/s41418-024-01407-1.
Chang Liu # 1,  Cheng Zhang # 2,  Hongkun Wu # 1,  Zhibin Zhao # 3,  Zhenhua Wang 1,  Xiaomin Zhang 1,  Jieli Yang 1,  Wenlong Yu 4,  Zhexiong Lian 5,  Minghui Gao 6,  Lin Zhou 7
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 2 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
  • 3 Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
  • 4 Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China. 909240168@qq.com.
  • 5 Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China. zxlian@gdph.org.cn.
  • 6 The HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. gaominghui@hit.edu.cn.
  • 7 Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China. lynnzhou36@163.com.
  • # Contributed equally.
PMID: 39478199 DOI: 10.1038/s41418-024-01407-1
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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