Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0050222 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4652 (Electronic) Linking ISSN: 00219541 NLM ISO Abbreviation: J Cell Physiol Subsets: MEDLINE

Publication: New York, NY : Wiley-Liss
Original Publication: Philadelphia, Wistar Institute of Anatomy and Biology.

Gemcitabine* ; Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; NF-E2-Related Factor 2*/metabolism ; NF-E2-Related Factor 2*/genetics ; Drug Resistance, Neoplasm*/genetics ; Drug Resistance, Neoplasm*/drug effects ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/pathology ; Carcinoma, Pancreatic Ductal*/drug therapy ; Carcinoma, Pancreatic Ductal*/genetics ; Carcinoma, Pancreatic Ductal*/pathology ; Ferroptosis*/drug effects ; Ferroptosis*/genetics ; Adenylosuccinate Lyase*/genetics ; Adenylosuccinate Lyase*/metabolism; Humans ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Antimetabolites, Antineoplastic/pharmacology ; Signal Transduction/drug effects

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.
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TMU111-AE1-B11 Taipei Medical University; MOST 112-2314-B-038 -053 Ministry of Science and Technology, Taiwan

Keywords: Carma3; Nrf2; adenylosuccinate lyase (ADSL); ferroptosis; gemcitabine resistance; pancreatic cancer

0 (Gemcitabine)
0W860991D6 (Deoxycytidine)
0 (NF-E2-Related Factor 2)
0 (NFE2L2 protein, human)
EC 4.3.2.2 (Adenylosuccinate Lyase)
0 (Antimetabolites, Antineoplastic)

Date Created: 20240821 Date Completed: 20241217 Latest Revision: 20241217

20241217

10.1002/jcp.31416

39164986