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SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

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.

SUBMITTER: Kim MJ

PROVIDER: S-EPMC10605569 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

Kim Myeong Jin MJ Kim Hyung Sun HS Kang Hyeon Woong HW Lee Da Eun DE Hong Woosol Chris WC Kim Ju Hyun JH Kim Minsoo M Cheong Jae-Ho JH Kim Hyo Jung HJ Park Joon Seong JS

Cells 20231023 20

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 pati ...[more]

PMID: 37887353

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE's potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) has the worst five-year overall survival rate among all cancer types. Acquired chemoresistance is considered one of the main reasons for this dismal prognosis, and the mechanism of chemoresistance is unknown.MethodsWe previously identified a subpopulation of chemoresistant CD44high-expressing PDAC cells. Subsequently, we selected the candidate gene, gamma-aminobutyric acid receptor subunit Pi (GABRP), from three Gene Expression Omnibus datasets as the potential CD44 downstream target mediating the gemcitabine resistance. Loss and gain of function such as stable knockdown of CD44 by small hairpin (sh) RNA-mediated silencing technique and overexpression (O/E) of CD44s had been studied for comparing the gemcitabine resistance among CD44high-expressing cells, shCD44 cells, CD44low-expressing cells and O/E CD44s expressing cells. Functional assays including cell viability, colony formation, invasion, quantitative PCR and western blotting techniques were performed to validate the roles of CD44 and GABRP playing in mediating the gemcitabine resistance in pancreatic cancer cells.ResultsCD44s depletion significantly reduced gemcitabine resistance in shCD44 single clone cells compared to CD44high-expressing cells. Knockdown of CD44 cells formed less colonies, became less invasive and remarkably decreased the mRNA level of GABRP. While overexpression of CD44s had the opposite effect on gemcitabine resistance, colony formation and invasive property. Of note, long term gemcitabine resistant pancreatic cancer cells detected increased expression of CD44 and GABRP. Clinically, GABRP expression was significantly upregulated in the tissues of patients with pancreatic cancer compared to the normal samples, and the overall survival rate of patients with low GABRP expression was longer. CD44 and GABRP co-expression was positively correlated in 178 pancreatic cancer patients.ConclusionOur findings suggest that GABRP may serve as a CD44s downstream target to diminish gemcitabine resistance in pancreatic cancer, and both CD44s and GABRP molecules have the potential to become prognostic biomarkers for PDAC patients with gemcitabine resistance.

Dataset Information

SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

Publications

SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

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