Kim, M.J.; Kim, H.S.; Kang, H.W.; Lee, D.E.; Hong, W.C.; Kim, J.H.; Kim, M.; Cheong, J.-H.; Kim, H.J.; Park, J.S. SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Cells2023, 12, 2509.
Kim, M.J.; Kim, H.S.; Kang, H.W.; Lee, D.E.; Hong, W.C.; Kim, J.H.; Kim, M.; Cheong, J.-H.; Kim, H.J.; Park, J.S. SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Cells 2023, 12, 2509.
Kim, M.J.; Kim, H.S.; Kang, H.W.; Lee, D.E.; Hong, W.C.; Kim, J.H.; Kim, M.; Cheong, J.-H.; Kim, H.J.; Park, J.S. SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Cells2023, 12, 2509.
Kim, M.J.; Kim, H.S.; Kang, H.W.; Lee, D.E.; Hong, W.C.; Kim, J.H.; Kim, M.; Cheong, J.-H.; Kim, H.J.; Park, J.S. SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer. Cells 2023, 12, 2509.
Abstract
Pancreatic cancer has a poor prognosis with its five-year survival rate lower than that of any other cancer type because it is difficult to detect in the early stages. 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 knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrated that SLC38A5 could be a novel therapeutic target to overcome gemcitabine-resistance in PDAC therapy.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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