CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in-vivo and in-vitro models

Schneiderhan, Wilhelm; Scheler, Mika; Kh, Holzmann; Marx, Maria; Gschwend, J. E.; Bucholz, M; Gress, Thomas M.; Seufferlein, Thomas; Adler, Guido; Oswald, Franz

doi:10.1055/s-0029-1241500

Cited by 16 publications

(23 citation statements)

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“…All together, these data lead to the conclusion that lactate constitutes a crucial energetic metabolite allowing fuel exchanges between hypoxic and normoxic compartments in the pancreatic tumor. A recent study, showing that alteration of MCT1 and MCT4 membrane trafficking by CD147 inhibition reduces the proliferation rate of aerobic glycolytic pancreatic cancer cells (22), strengthens the fact that the export of lactate by hypoxic cells and its uptake by normoxic ones are essential for the malignant phenotype of PDAC.…”

Section: Characterization Of Hypoxic Regions In Pdacmentioning

confidence: 80%

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

Guillaumond

Leca

Olivares

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

353

342

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Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.pancreas | malignancy | metabolism | glutamate N inety-five percent of patients with pancreatic cancer harbor tumors classified as pancreatic ductal adenocarcinoma (PDAC). Commonly described as a silent killer regarding its late diagnosis, PDAC is noted for its aggressiveness and its intrinsic resistance to standard chemotherapy. This specificity is probably due to a low vascular density and a prominent nontumoral cell compartment (stroma), which impact on intratumoral perfusion, therapeutic delivery, and patient outcome (1). Indeed, PDAC is characterized by numerous and severe hypoxic regions (2), a feature that has been proven to be correlated with tumor aggressiveness and poor prognosis compared with well-oxygenated tumors (3). Moreover, combined with hypoxia, the subsequent nutrient-devoid environment provides physiological selective pressure promoting expansion of the most aggressive malignant cells, particularly those acquiring mutations in genes encoding tumor suppressor protein p53 (TP53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog protein (KRAS) (4, 5), two of the main mutations present in PDAC patients. Regarding such statements, it appears relevant to deeply explore consequ...

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Section: Characterization Of Hypoxic Regions In Pdacmentioning

confidence: 80%

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

Guillaumond

Leca

Olivares

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

353

342

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“…This correlates with high levels of GLUT1 in MiaPaCa-2 cells compared with the PDAC cell lines BxPC-3 and Panc-1 (32,33). The proliferation of human PDAC cell lines MiaPaCa-2 and Panc-1 is blocked by inhibitors of glycolysis (31,33). Moreover, MiaPaCa-2 and Panc-1 cells are strictly dependent on glutamine for growth (34).…”

Section: Discussionmentioning

confidence: 93%

“…In PDAC, MiaPaCa-2 cells have been shown to exhibit a very high rate of lactate production (31). This correlates with high levels of GLUT1 in MiaPaCa-2 cells compared with the PDAC cell lines BxPC-3 and Panc-1 (32,33).…”

Section: Discussionmentioning

confidence: 99%

Hyper-O-GlcNAcylation Is Anti-apoptotic and Maintains Constitutive NF-κB Activity in Pancreatic Cancer Cells

Vocadlo

Vosseller

2013

Journal of Biological Chemistry

218

219

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Background: Cancer cells rely on energy metabolism that requires increased glucose uptake and constitutive NF-B activity for survival. Results: Pancreatic cancer cells display elevated O-GlcNAcylation, reduction of which inhibits cell survival and oncogenic NF-B signaling. Conclusion: Hyper-O-GlcNAcylation is anti-apoptotic and contributes to NF-B activation in pancreatic cancer. Significance: Targeting hyper-O-GlcNAcylation may serve as a novel therapeutic intervention in pancreatic cancer.

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“…In addition to EMMPRIN content, it is also of interest that the levels of EMMPRIN-interacting proteins are also diminished (Figs. 6, 8), including MCT-1 that regulates lactate transport and T cell proliferation (15,54,55), CD98, and b1-integrin, implying a deficiency in the ability of leukocytes to adhere, and MMP-9/TIMP-1 ratio. Interestingly, MMP-9 levels were not affected between groups, however, TIMP-1 expression (an endogenous inhibitor of MMP activity) was increased in the minocycline-treated splenocytes compared with the EAE-only controls at preonset (Fig.…”

Section: Discussionmentioning

confidence: 99%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

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CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in-vivo and in-vitro models

Cited by 16 publications

References 0 publications

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

Hyper-O-GlcNAcylation Is Anti-apoptotic and Maintains Constitutive NF-κB Activity in Pancreatic Cancer Cells

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

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