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SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer

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 b...

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Autores principales: Kim, Myeong Jin, Kim, Hyung Sun, Kang, Hyeon Woong, Lee, Da Eun, Hong, Woosol Chris, Kim, Ju Hyun, Kim, Minsoo, Cheong, Jae-Ho, Kim, Hyo Jung, Park, Joon Seong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605569/
https://www.ncbi.nlm.nih.gov/pubmed/37887353
http://dx.doi.org/10.3390/cells12202509
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author Kim, Myeong Jin
Kim, Hyung Sun
Kang, Hyeon Woong
Lee, Da Eun
Hong, Woosol Chris
Kim, Ju Hyun
Kim, Minsoo
Cheong, Jae-Ho
Kim, Hyo Jung
Park, Joon Seong
author_facet Kim, Myeong Jin
Kim, Hyung Sun
Kang, Hyeon Woong
Lee, Da Eun
Hong, Woosol Chris
Kim, Ju Hyun
Kim, Minsoo
Cheong, Jae-Ho
Kim, Hyo Jung
Park, Joon Seong
author_sort Kim, Myeong Jin
collection PubMed
description 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.
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spelling pubmed-106055692023-10-28 SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer Kim, Myeong Jin Kim, Hyung Sun Kang, Hyeon Woong Lee, Da Eun Hong, Woosol Chris Kim, Ju Hyun Kim, Minsoo Cheong, Jae-Ho Kim, Hyo Jung Park, Joon Seong Cells Article 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. MDPI 2023-10-23 /pmc/articles/PMC10605569/ /pubmed/37887353 http://dx.doi.org/10.3390/cells12202509 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Myeong Jin
Kim, Hyung Sun
Kang, Hyeon Woong
Lee, Da Eun
Hong, Woosol Chris
Kim, Ju Hyun
Kim, Minsoo
Cheong, Jae-Ho
Kim, Hyo Jung
Park, Joon Seong
SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title_full SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title_fullStr SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title_full_unstemmed SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title_short SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer
title_sort slc38a5 modulates ferroptosis to overcome gemcitabine resistance in pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605569/
https://www.ncbi.nlm.nih.gov/pubmed/37887353
http://dx.doi.org/10.3390/cells12202509
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