دورية أكاديمية
Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: exploiting this novel finding as a potential target
| العنوان: | Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: exploiting this novel finding as a potential target |
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| المؤلفون: | Gampala, Silpa, Shah, Fenil, Lu, Xiaoyu, Moon, Hye-ran, Babb, Olivia, Umesh Ganesh, Nikkitha, Sandusky, George, Hulsey, Emily, Armstrong, Lee, Mosely, Amber L., Han, Bumsoo, Ivan, Mircea, Yeh, Jing-Ruey Joanna, Kelley, Mark R., Zhang, Chi, Fishel, Melissa L. |
| المساهمون: | Pediatrics, School of Medicine |
| المصدر: | PMC |
| بيانات النشر: | BMC |
| سنة النشر: | 2021 |
| المجموعة: | Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| مصطلحات موضوعية: | scRNA-seq, Ref-1, Redox function, Metabolism, Cancer associated fibroblasts (CAFs), Pancreatic cancer, Mitochondria |
| الوصف: | Background: Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy. Redox factor-1 (Ref-1), a redox signaling protein, regulates the conversion of several transcription factors (TFs), including HIF-1α, STAT3 and NFκB from an oxidized to reduced state leading to enhancement of their DNA binding. In our previously published work, knockdown of Ref-1 under normoxia resulted in altered gene expression patterns on pathways including EIF2, protein kinase A, and mTOR. In this study, single cell RNA sequencing (scRNA-seq) and proteomics were used to explore the effects of Ref-1 on metabolic pathways under hypoxia. Methods: scRNA-seq comparing pancreatic cancer cells expressing less than 20% of the Ref-1 protein was analyzed using left truncated mixture Gaussian model and validated using proteomics and qRT-PCR. The identified Ref-1's role in mitochondrial function was confirmed using mitochondrial function assays, qRT-PCR, western blotting and NADP assay. Further, the effect of Ref-1 redox function inhibition against pancreatic cancer metabolism was assayed using 3D co-culture in vitro and xenograft studies in vivo. Results: Distinct transcriptional variation in central metabolism, cell cycle, apoptosis, immune response, and genes downstream of a series of signaling pathways and transcriptional regulatory factors were identified in Ref-1 knockdown vs Scrambled control from the scRNA-seq data. Mitochondrial DEG subsets downregulated with Ref-1 knockdown were significantly reduced following Ref-1 redox inhibition and more dramatically in combination with Devimistat in vitro. Mitochondrial function assays demonstrated that Ref-1 knockdown and Ref-1 redox signaling inhibition decreased utilization of TCA cycle substrates and slowed the growth of pancreatic cancer co-culture spheroids. In Ref-1 knockdown cells, a higher flux rate of ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | Journal of Experimental & Clinical Cancer Research; Gampala S, Shah F, Lu X, et al. Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: exploiting this novel finding as a potential target. J Exp Clin Cancer Res. 2021;40(1):251. Published 2021 Aug 10. doi:10.1186/s13046-021-02046-x; https://hdl.handle.net/1805/31410Test |
| الإتاحة: | https://doi.org/10.1186/s13046-021-02046-xTest https://hdl.handle.net/1805/31410Test |
| حقوق: | Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.EB1E9222 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |