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SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer

Authors
 Myeong Jin Kim  ;  Hyung Sun Kim  ;  Hyeon Woong Kang  ;  Da Eun Lee  ;  Woosol Chris Hong  ;  Ju Hyun Kim  ;  Minsoo Kim  ;  Jae-Ho Cheong  ;  Hyo Jung Kim  ;  Joon Seong Park 
Citation
 CELLS(Cells), Vol.12(20) : 2509, 2023-10 
Journal Title
CELLS(Cells)
ISSN
 2073-4409 
Issue Date
2023-10
MeSH
Amino Acid Transport Systems, Neutral* ; Animals ; Cell Line, Tumor ; Deoxycytidine / pharmacology ; Deoxycytidine / therapeutic use ; Drug Resistance, Neoplasm ; Ferroptosis* ; Gemcitabine ; Glutamine ; Humans ; Mice ; Pancreatic Neoplasms* / drug therapy ; Pancreatic Neoplasms* / genetics ; Pancreatic Neoplasms* / metabolism
Keywords
PDAC ; SLC38A5 ; ferroptosis ; gemcitabine resistance ; lipid ROS
Abstract
Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed that knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrate that SLC38A5 could be a novel target to overcome gemcitabine resistance in PDAC therapy. © 2023 by the authors.
Files in This Item:
T999202676.pdf Download
DOI
10.3390/cells12202509
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyung Sun(김형선) ORCID logo https://orcid.org/0000-0002-9002-3569
Kim, Hyo Jung(김효정) ORCID logo https://orcid.org/0000-0002-3514-1247
Park, Joon Seong(박준성) ORCID logo https://orcid.org/0000-0001-8048-9990
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/198476
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