scholarly journals KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism

2021 ◽  
Vol 22 (10) ◽  
pp. 5070
Author(s):  
Isaac James Muyinda ◽  
Jae Gwang Park ◽  
Eun Jung Jang ◽  
Byong Chul Yoo
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Early Stage ◽  
Lipid Synthesis ◽  
Metabolic Reprogramming ◽  
Treatment Modalities ◽  
Early Stage Disease ◽  
Pancreatic Cancer Cells ◽  
Citrate Metabolism

Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells.

Abstract 2353: Metabolic reprogramming by SLC1A5 downregulation in pancreatic cancer cells

2021 ◽  
Author(s):  
Raj Kumar Sharma ◽  
Balalji Krishnamachary ◽  
Ishwarya Sivakumar ◽  
Yelena Mironchik ◽  
Santosh Kumar Bharti ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metabolic Reprogramming ◽  
Pancreatic Cancer Cells

Abstract 4353: Stroma drive metabolic reprogramming and induces stemness properties in pancreatic cancer cells

2019 ◽  
Author(s):  
Kousik K. Kesh ◽  
Vineet K. Gupta ◽  
Nikita Sharma ◽  
Roey Hadad ◽  
Vikas Dudeja ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metabolic Reprogramming ◽  
Pancreatic Cancer Cells

Abstract 4353: Stroma drive metabolic reprogramming and induces stemness properties in pancreatic cancer cells

2019 ◽  
Author(s):  
Kousik K. Kesh ◽  
Vineet K. Gupta ◽  
Nikita Sharma ◽  
Roey Hadad ◽  
Vikas Dudeja ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metabolic Reprogramming ◽  
Pancreatic Cancer Cells

scholarly journals Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells

2020 ◽  
Vol 477 (10) ◽  
pp. 1923-1937 ◽  
Author(s):  
Aimin Cai ◽  
Hailun Zheng ◽  
Zhiwei Chen ◽  
Xinlu Lin ◽  
Chen Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acid ◽  
Cancer Cells ◽  
1H Nmr ◽  
Metabolic Pathways ◽  
Pancreatic Cancer Cell Line ◽  
Metabolite Profile ◽  
Human Pancreatic Cancer ◽  
Combination Regimen ◽  
Pancreatic Cancer Cells

Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.

scholarly journals Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

2020 ◽  
Author(s):  
Kousik Kesh ◽  
Vanessa T Garrido ◽  
Austin Doesch ◽  
Brittany Durden ◽  
Vineet K Gupta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Metabolic Pathways ◽  
Pancreatic Tumor ◽  
Tumor Regression ◽  
Metabolic Reprogramming ◽  
Pancreatic Tumors ◽  
Glycolytic Flux ◽  
M2 Macrophages ◽  
Pancreatic Cancer Cells

AbstractPancreatic adenocarcinoma is a devastating disease with an abysmal survival rate of 9%. A robust fibro-inflammatory and desmoplastic stroma, characteristic of pancreatic cancer, contributes to the challenges in developing viable therapeutic strategies in this disease. Apart from constricting blood vessels and preventing efficient drug delivery to the tumor, the stroma also contributes to aggressive biology of the cancer along with its immune-evasive microenvironment. In this study, we show that in pancreatic tumors, the developing stroma increases tumor initiation frequency in pancreatic cancer cells in vivo by enriching for CD133+ aggressive “stem-like” cells. Additionally, the stromal fibroblasts secrete IL6 as the major cytokine, increases glycolytic flux in the pancreatic tumor cells and increases lactate efflux in the microenvironment via activation of the STAT signaling pathway. We also show that the secreted lactate favors activation of M2 macrophages in the tumor microenvironment, which excludes CD8+ T-cells in the tumor. Our data additionally confirms that treatment of pancreatic tumors with anti-IL6 antibody results in tumor regression as well as decreased CD133+ population within the tumor. Furthermore, inhibiting the lactate efflux in the microenvironment reduces M2 macrophages, and makes pancreatic tumors more responsive to anti-PD1 therapy. This suggests that stromal IL6 driven metabolic reprogramming plays a significant role in the development of an immune evasive microenvironment. In conclusion, our study shows that targeting the metabolic pathways affected by stromal IL6 can make pancreatic tumors amenable to checkpoint inhibitor therapy.

scholarly journals Highly sensitive and portable mRNA detection platform for early cancer detection

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hongxia Li ◽  
Antony R. Warden ◽  
Wenqiong Su ◽  
Jie He ◽  
Xiao Zhi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Early Stage ◽  
Point Of Care ◽  
Cancer Biomarker ◽  
Detection Sensitivity ◽  
Detection Methods ◽  
Mrna Detection ◽  
Amplification Method ◽  
Pancreatic Cancer Cells

AbstractPancreatic cancer, at unresectable advanced stages, presents poor prognoses, which could be prevented by early pancreatic cancer diagnosis methods. Recently, a promising early-stage pancreatic cancer biomarker, extracellular vesicles (EVs) related glypican-1 (GPC1) mRNA, is found to overexpress in pancreatic cancer cells. Current mRNA detection methods usually require expensive machinery, strict preservation environments, and time-consuming processes to guarantee detection sensitivity, specificity, and stability. Herein, we propose a novel two-step amplification method (CHAGE) via the target triggered Catalytic Hairpin Assembly strategy combined with Gold-Enhanced point-of-care-testing (POCT) technology for sensitive visual detection of pancreatic cancer biomarker. First, utilizing the catalyzed hairpin DNA circuit, low expression of the GPC1 mRNA was changed into amplification product 1 (AP1, a DNA duplex) as the next detection targets of the paper strips. Second, the AP1 was loaded onto a lateral flow assay and captured with the gold signal nanoparticles to visualize results. Finally, the detected results can be further enhanced by depositing gold to re-enlarge the sizes of gold nanoparticles in detection zones. As a result, the CHAGE methodology lowers the detection limit of mRNA to 100 fM and provides results within 2 h at 37 °C. Furthermore, we demonstrate the successful application in discriminating pancreatic cancer cells by analyzing EVs’ GPC1 mRNA expression levels. Hence, the CHAGE methodology proposed here provides a rapid and convenient POCT platform for sensitive detection of mRNAs through unique probes designs (COVID, HPV, etc.).

ERO1α promotes hypoxic tumour progression and is associated with poor prognosis in pancreatic cancer

2019 ◽  
Author(s):  
Nikhil Gupta ◽  
Jung Eun Park ◽  
Wilford Tse ◽  
Jee Keem Low ◽  
Oi Lian Kon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumour Progression ◽  
Xenograft Model ◽  
Early Stage Disease ◽  
Hypoxia Stress ◽  
Pancreatic Cancer Cells ◽  
Proteomic Approach ◽  
Mouse Xenograft Model

AbstractPancreatic cancer is a leading cause of mortality worldwide due to difficulty detecting early-stage disease and our poor understanding of the mediators that drive the progression of hypoxic solid tumours. We, therefore, used a heavy isotope ‘pulse/trace’ proteomic approach to determine how hypoxia alters pancreatic tumour expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistant (ABCB6), immune suppression (NFIL3,WDR4), angiogenesis (ANGPT4, ERO1α, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1α was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1α substantially reduced growth rates and colony formation in pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1α-deficient tumour cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1α is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.

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