CHES1 modulated tumorigenesis and senescence of pancreas cancer cells through repressing AKR1B10

Demin Kong; Yingying Wu; Binghua Tong; Yonghui Liang; Fuyi Xu; Xiaodong Chi; Lei Ni; Geng Tian; Guilong Zhang; Zhaowei Xu

doi:10.1016/j.bbadis.2024.167214

CHES1 modulated tumorigenesis and senescence of pancreas cancer cells through repressing AKR1B10

Biochim Biophys Acta Mol Basis Dis. 2024 May 6;1870(6):167214. doi: 10.1016/j.bbadis.2024.167214. Online ahead of print.

Authors

Affiliations

¹ Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, China.
² Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, China; The Second Medical College, Binzhou Medical University, Yantai, China.
³ Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, School of Pharmacy, Binzhou Medical University, Yantai, China. Electronic address: zhaoweixv@bzmc.edu.cn.

PMID: 38718846
DOI: 10.1016/j.bbadis.2024.167214

Abstract

Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.

Keywords: AKR1B10; CHES1; Gemcitabine; PDAC; Senescence.