2. Academic Validation
  3. INHBA promotes chemoresistance in pancreatic cancer by enhancing CTPS1 stability and mediating pyrimidine metabolism

INHBA promotes chemoresistance in pancreatic cancer by enhancing CTPS1 stability and mediating pyrimidine metabolism

  • Cancer Cell Int. 2025 Nov 14;25(1):403. doi: 10.1186/s12935-025-03984-8.
Xinghao Sun # 1 2 3 4 5 6,  Zikai Wei # 1 2 3 4 5 6,  Xingkun Liao # 1 2 3 4 5 6,  Dijie Zheng 1 3 4 5,  Futang Li 1 2 3 4 5,  Liwen Chen 1 2 3 4 5,  Yanyu Gong 1 2 3 4 5,  Suye Ran 1 3 4 5,  Xiaozhao Han 1 2 3 4 5,  Zhiwei He 7 8,  Chao Yu 9 10 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, 550001, China.
  • 2 College of Clinical Medicine, Guizhou Medical University, Guiyang, 550001, China.
  • 3 Guizhou Provincial Institute of Hepatobiliary, Pancreatic and Splenic Diseases, Guiyang, 550001, China.
  • 4 Key Laboratory of Liver, Pancreas and Spleen of Guizhou Medical University, Gallbladder, Guiyang, 550001, China.
  • 5 Guizhou Provincial Clinical Medical Research Center of Hepatobiliary Surgery, Guiyang, 550004, Guizhou, China.
  • 6 Department of Hepatic Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
  • 7 Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, 518000, China. [email protected].
  • 8 Department of Hepatic Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. [email protected].
  • 9 Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, 550001, China. [email protected].
  • 10 College of Clinical Medicine, Guizhou Medical University, Guiyang, 550001, China. [email protected].
  • 11 Guizhou Provincial Institute of Hepatobiliary, Pancreatic and Splenic Diseases, Guiyang, 550001, China. [email protected].
  • 12 Key Laboratory of Liver, Pancreas and Spleen of Guizhou Medical University, Gallbladder, Guiyang, 550001, China. [email protected].
  • 13 Guizhou Provincial Clinical Medical Research Center of Hepatobiliary Surgery, Guiyang, 550004, Guizhou, China. [email protected].
  • 14 Key Laboratory of Hepatobiliary and Pancreatic Diseases Treatment and Bioinformatics Research, Guizhou Medical University, Guiyang, 550001, China. [email protected].
  • # Contributed equally.
PMID: 41239468 DOI: 10.1186/s12935-025-03984-8
Abstract

Background: Gemcitabine is the primary chemotherapeutic agent used as a first-line treatment for pancreatic Cancer (PC), underscoring its pivotal role in Cancer treatment. This drug induces Apoptosis through multiple mechanisms, with the disruption of cellular pyrimidine metabolism being a crucial mode of action. However, gemcitabine resistance significantly limits the long-term efficacy of PC treatments. Our study aimed to identify potential targets for gemcitabine sensitization.

Methods: We identified a gene set associated with pyrimidine metabolism through cluster analysis of The Cancer Genome Atlas Pancreatic Adenocarcinoma database. Intersecting this set of differentially upregulated genes in PC with normal tissues revealed inhibin βA (INHBA) as a gene related to pyrimidine metabolism. Quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry analyses confirmed INHBA overexpression in PC cells. INHBA's effects of INHBA on cell proliferation and chemoresistance in PC cells were validated in vitro using a colony counting kit-8 assay, drug sensitivity analysis, EdU incorporation, flow cytometry, and colony formation assay. The proliferation and chemoresistance promotion by INHBA in PC cells was validated in vivo using a mouse xenograft model. Downstream targets of INHBA were identified using immunoprecipitation mass spectrometry.

Results: INHBA, a pyrimidine metabolism-associated gene, was highly expressed in PC, and its expression correlated with gemcitabine resistance. INHBA interacts with cytidine triphosphate synthase 1 (CTPS1) and competitively inhibits SMAD Specific E3 Ubiquitin Protein Ligase 1 mediated ubiquitination, enhancing CTPS1 stability and promoting pyrimidine metabolism.

Conclusion: INHBA promotes gemcitabine resistance in PC by stabilizing CTPS1 and enhancing pyrimidine metabolism, making it a potential target for chemosensitization in PC.

Keywords

Gemcitabine resistance; INHBA; Pancreatic cancer; Pyrimidine metabolism.

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