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      Phosphomimetic Dicer S1016E triggers a switch to glutamine metabolism in gemcitabine-resistant pancreatic cancer

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          Abstract

          Objective

          Dicer is an enzyme that processes microRNAs (miRNAs) precursors into mature miRNAs, which have been implicated in various aspects of cancer progressions, such as clinical aggressiveness, prognosis, and survival outcomes. We previously showed that high expression of Dicer is associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC); thus, in this study, we aimed to focus on how Dicer is involved in GEM resistance in PDAC, including cancer prognosis, cell proliferation, and metabolic regulation.

          Methods

          We generated stable shRNA knockdown of Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells and explored cell viability by MTT and clonogenicity assays. Metabolomic profiling was employed to investigate metabolic changes between parental cells, PANC-1, and PANC-1 GR cells, and further implied to compare their sensitivity to the glutaminase inhibitor, CB839, and GEM treatments. To identify putative phosphorylation site involves with Dicer and its effects on GEM resistance in PDAC cells, we further generated phosphomimetic or phosphomutant Dicer at S1016 site and examined the changes in drug sensitivity, metabolic alteration, and miRNA regulation.

          Results

          We observed that high Dicer levels in pancreatic ductal adenocarcinoma cells were positively correlated with advanced pancreatic cancer and acquired resistance to GEM. Metabolomic analysis indicated that PANC-1 GR cells rapidly utilised glutamine as their major fuel and increased levels of glutaminase ( GLS): glutamine synthetase ( GLUL) ratio which is related to high Dicer expression. In addition, we found that phosphomimetic Dicer S1016E but not phosphomutant Dicer S1016A facilitated miRNA maturation, causing an imbalance in GLS and GLUL and resulting in an increased response to GLS inhibitors.

          Conclusion

          Our results suggest that phosphorylation of Dicer on site S1016 affects miRNA biogenesis and glutamine metabolism in GEM-resistant pancreatic cancer.

          Highlights

          • Dicer expression is positively correlated with advanced pancreatic cancer.

          • Dicer expression is significantly correlated with high level of GLS and GLS/GLUL ratio.

          • Phosphomimetic Dicer S1016E enhances glutamine consumption and GLS inhibitor sensitivity.

          • Phosphomimetic Dicer S1016E facilitates miRNAs maturation to increase GLS/GLUL ratio.

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          Most cited references46

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          Cancer statistics, 2020

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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            Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles.

            DNA microarrays have been widely applied to cancer transcriptome analysis; however, the majority of such data are not easily accessible or comparable. Furthermore, several important analytic approaches have been applied to microarray analysis; however, their application is often limited. To overcome these limitations, we have developed Oncomine, a bioinformatics initiative aimed at collecting, standardizing, analyzing, and delivering cancer transcriptome data to the biomedical research community. Our analysis has identified the genes, pathways, and networks deregulated across 18,000 cancer gene expression microarrays, spanning the majority of cancer types and subtypes. Here, we provide an update on the initiative, describe the database and analysis modules, and highlight several notable observations. Results from this comprehensive analysis are available at http://www.oncomine.org.
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              Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway

              Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts 1 . Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes 2 . Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as Gln deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumors.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                19 August 2022
                November 2022
                19 August 2022
                : 65
                : 101576
                Affiliations
                [1 ]Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan
                [2 ]Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
                [3 ]Taipei Medical University and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Cancer Center, Taipei Medical University, Taiwan
                [4 ]Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
                [5 ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [6 ]Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
                [7 ]Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [8 ]Taipei Medical University Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
                [9 ]TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan
                [10 ]Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
                [11 ]Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan
                [12 ]Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                [13 ]Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                Author notes
                []Corresponding author. Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei 11031, Taiwan. Fax: +886 2 2737 3112. chiucf@ 123456tmu.edu.tw
                Article
                S2212-8778(22)00145-4 101576
                10.1016/j.molmet.2022.101576
                9460536
                35995401
                136dc728-2561-4cbe-bdea-a055596c9897
                © 2022 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 7 June 2022
                : 8 August 2022
                : 13 August 2022
                Categories
                Original Article

                dicer phosphorylation,pancreatic ductal adenocarcinoma,gemcitabine resistance,glutamine metabolism,mirna biogenesis

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