MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

Shukla, Surendra K.; Purohit, Vinee; Mehla, Kamiya; Gunda, Venugopal; Chaika, Nina V.; Vernucci, Enza; King, Ryan J.; Abrego, Jaime; Goode, Gennifer D.; Dasgupta, Aneesha; Illies, Alysha L.; Gebregiworgis, Teklab; Dai, Bingbing; Augustine, Jithesh J.; Murthy, Divya; Attri, Kuldeep S.; Mashadova, Oksana; Grandgenett, Paul M.; Powers, Robert; Ly, Quan P.; Lazenby, Audrey J.; Grem, Jean L.; Yu, Fang; Matés, José M.; Asara, John M.; Kim, Jung-whan; Hankins, Jordan; Weekes, Colin D.; Hollingsworth, Michael A.; Serkova, Natalie J.; Sasson, Aaron R.; Fleming, Jason B.; Oliveto, Jennifer; Lyssiotis, Costas A.; Cantley, Lewis C.; Berim, Lyudmyla; Singh, Pankaj K.

doi:10.1016/j.ccell.2017.08.008

Cited by 91 publications

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“…To achieve a comprehensive understanding of metabolic changes in response to viral challenge, we challenged mouse bone marrow-derived macrophages (BMMs) with vesicular stomatitis virus (VSV) and performed metabolomics assay (Shukla et al, 2017). Principal component analysis revealed a markedly altered metabolic profile induced by VSV (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

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O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

Attri

et al. 2018

Cell Host & Microbe

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117

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SUMMARY Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation, but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSV) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, OGT-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 (S366) is required for K63-linked ubiquitination of MAVS and subsequent downstream RLR-antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism on antiviral innate immunity.

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Section: Resultsmentioning

confidence: 99%

“…The metabolite extraction was performed as previously described (Gunda et al, 2016; Shukla et al, 2017). The media was aspirated, and the cells were washed twice with LC-MS grade water to remove media remnants before lysing the cells.…”

Section: Methodsmentioning

confidence: 99%

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

Attri

et al. 2018

Cell Host & Microbe

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117

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“…According to known reports, the flux increase to PPP is said to be involved in gemcitabine resistance, which is a nucleic acid antagonist. It is also conceivable that a decrease in MPC1 may result in gemcitabine resistance …”

Section: Discussionmentioning

confidence: 99%

“…As part of it, HIF‐1 is considered to cause hyperexpression in the hypoxic region of cancer, but the HIF‐1α control glycolysis system increases metabolite flux to PPP. Increased flux to PPP has been reported to affect radioresistance and gemcitabine (a nucleic acid antimetabolite) tolerance . Radiation therapy, chemotherapy, and chemoradiation therapy as well as surgery are the most fundamental treatments in today's cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial pyruvate carrier 1 expression controls cancer epithelial‐mesenchymal transition and radioresistance

et al. 2019

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Mitochondrial pyruvate carrier (MPC) is known to cause different expressions in normal and cancer cells. We observed a change in phenotype with the suppression of MPC expression. We knocked down MPC1 and/or MPC2 using siRNA or shRNA. We observed its cell morphology and accompanying molecular marker. Furthermore, the radioresistance of the MPC knockdown cell line was examined using a colony formation assay. MPC1‐suppressed cells changed their morphology to a spindle shape. Epithelial‐mesenchymal transition (EMT) was suspected, and examination of the EMT marker by PCR showed a decrease in E‐cadherin and an increase in fibronectin. Focusing on glutamine metabolism as the mechanism of this phenomenon, we knocked down the glutamine‐metabolizing enzyme glutaminase (GLS). EMT was also observed in GLS‐suppressed cells. Furthermore, when MPC1‐suppressed cells were cultured in a glutamine‐deficient medium, changes in EMT markers were suppressed. In addition, MPC1‐suppressed cells also increased with a significant difference in radioresistance. Decreased MPC1 expression favorably affects EMT and radioresistance of cancer.

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“…A recent finding by Shukla and colleagues adds to the understanding of the poor clinical response by demonstrating a HIF1 dependent metabolic adaption that results in resistance to gemcitabine, a standard of care in PDA. Through increased pyrimidine biosynthesis imparted by MUC-1/HIF1 crosstalk, PDA tumors develop resistance to gemcitabine [92]. These results demonstrate another instance where the plasticity of PDA metabolism leads to treatment resistance, yet highlights potential therapeutic targets that may improve clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

Biancur

Kimmelman

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that is highly refractory to the current standards of care. The difficulty in treating this disease is due to a number of different factors, including altered metabolism. In PDA, the metabolic rewiring favors anabolic reactions which supply the cancer cell with necessary cellular building blocks for unconstrained growth. Furthermore, PDA cells display high levels of basal autophagy and macropinocytosis. KRAS is the driving oncogene in PDA and many of the metabolic changes are downstream of its activation. Together, these unique pathways for nutrient utilization and acquisition result in metabolic plasticity enabling cells to rapidly adapt to nutrient and oxygen fluctuations. This remarkable adaptability has been implicated as a cause of the intense therapeutic resistance. In this review, we discuss metabolic pathways in PDA tumors and highlight how they contribute to the pathogenesis and treatment of the disease.

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MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer

Abstract: In the originally published version of the paper, author Natalie J. Serkova's name was spelled incorrectly as ''Sarkova.'' The correct spelling of the name is ''Serkova,'' and the error has been corrected in the original article online. The authors apologize for this error.

Cited by 91 publications

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O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

Mitochondrial pyruvate carrier 1 expression controls cancer epithelial‐mesenchymal transition and radioresistance

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

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