Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)
| Autor: | In-Whan Oh, Pishyaporn Sritangos, Thomas Attard, Andrew D. James, Jason I.E. Bruce, Daniel A Richardson, Lisa Barrett |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Programmed cell death Thyroid Hormones Cell Survival Calcium pump Cell PKM2 Article 03 medical and health sciences 0302 clinical medicine Adenosine Triphosphate Cytosol Cell Movement Cell Line Tumor medicine Humans Glycolysis Pancreas 030304 developmental biology Cell Proliferation 0303 health sciences Chemistry Cell growth Calcium signalling Membrane Proteins Cancer metabolism Cell biology Pancreatic Neoplasms medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Calcium Carrier Proteins Pyruvate kinase Carcinoma Pancreatic Ductal Naphthoquinones |
| Zdroj: | British Journal of Cancer James, A, Richardson, D A, Oh, I-W, Sritangos, P, Attard, T, Barrett, L & Bruce, J 2019, ' Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: Role of pyruvate kinase-M2 (PKM2) ', BJC . https://doi.org/10.1038/s41416-019-0675-3 |
| ISSN: | 1532-1827 |
| DOI: | 10.1038/s41416-019-0675-3 |
| Popis: | Background Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca2+-dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed in PDAC. This study investigated the PKM2-derived ATP supply to the PMCA as a potential therapeutic locus. Methods PDAC cell growth, migration and death were assessed by using sulforhodamine-B/tetrazolium-based assays, gap closure assay and poly-ADP ribose polymerase (PARP1) cleavage, respectively. Cellular ATP and metabolism were assessed using luciferase/fluorescent-based assays and the Seahorse XFe96 analyzer, respectively. Cell surface biotinylation identified membrane-associated proteins. Fura-2 imaging was used to assess cytosolic Ca2+ overload and in situ Ca2+ clearance. PKM2 knockdown was achieved using siRNA. Results The PKM2 inhibitor (shikonin) reduced PDAC cell proliferation, cell migration and induced cell death. This was due to inhibition of glycolysis, ATP depletion, inhibition of PMCA and cytotoxic Ca2+ overload. PKM2 associates with plasma membrane proteins providing a privileged ATP supply to the PMCA. PKM2 knockdown reduced PMCA activity and reduced the sensitivity of shikonin-induced cell death. Conclusions Cutting off the PKM2-derived ATP supply to the PMCA represents a novel therapeutic strategy for the treatment of PDAC. |
| Databáze: | OpenAIRE |
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