Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells
Cancer utilization of large glutamine equivalents contributes to diverging glucose-6-P flux toward the pentose phosphate shunt (PPP) to feed the building blocks and the antioxidant responses of rapidly proliferating cells. In addition to the well-acknowledged cytosolic pathway, cancer cells also run...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/1/43 |
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| author | Cecilia Marini Vanessa Cossu Sonia Carta Elisa Greotti Daniela Gaglio Nadia Bertola Sabrina Chiesa Silvia Bruno Francesca Vitale Marcella Bonanomi Danilo Porro Mattia Riondato Anna Maria Orengo Matteo Bauckneht Silvia Morbelli Silvia Ravera Gianmario Sambuceti |
| author_facet | Cecilia Marini Vanessa Cossu Sonia Carta Elisa Greotti Daniela Gaglio Nadia Bertola Sabrina Chiesa Silvia Bruno Francesca Vitale Marcella Bonanomi Danilo Porro Mattia Riondato Anna Maria Orengo Matteo Bauckneht Silvia Morbelli Silvia Ravera Gianmario Sambuceti |
| author_sort | Cecilia Marini |
| collection | DOAJ |
| description | Cancer utilization of large glutamine equivalents contributes to diverging glucose-6-P flux toward the pentose phosphate shunt (PPP) to feed the building blocks and the antioxidant responses of rapidly proliferating cells. In addition to the well-acknowledged cytosolic pathway, cancer cells also run a largely independent PPP, triggered by hexose-6P-dehydrogenase within the endoplasmic reticulum (ER), whose activity is mandatory for the integrity of ER–mitochondria networking. To verify whether this reticular metabolism is dependent on glutamine levels, we complemented the metabolomic characterization of intermediates of the glucose metabolism and tricarboxylic acid cycle with the estimation of proliferating activity, energy metabolism, redox damage, and mitochondrial function in two breast cancer cell lines. ER-PPP activity and its determinants were estimated by the ER accumulation of glucose analogs. Glutamine shortage decreased the proliferation rate despite increased ATP and NADH levels. It depleted NADPH reductive power and increased malondialdehyde content despite a marked increase in glucose-6P-dehydrogenase. This paradox was explained by the deceleration of ER-PPP favored by the decrease in hexose-6P-dehydrogenase expression coupled with the opposite response of its competitor enzyme glucose-6P-phosphatase. The decreased ER-PPP activity eventually hampered mitochondrial function and calcium exchanges. These data configure the ER-PPP as a powerful, unrecognized regulator of cancer cell metabolism and proliferation. |
| first_indexed | 2024-03-09T13:47:23Z |
| format | Article |
| id | doaj.art-a14e2a4738834663a2fa6884d6f14854 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T13:47:23Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-a14e2a4738834663a2fa6884d6f148542023-11-30T20:57:31ZengMDPI AGAntioxidants2076-39212022-12-011214310.3390/antiox12010043Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer CellsCecilia Marini0Vanessa Cossu1Sonia Carta2Elisa Greotti3Daniela Gaglio4Nadia Bertola5Sabrina Chiesa6Silvia Bruno7Francesca Vitale8Marcella Bonanomi9Danilo Porro10Mattia Riondato11Anna Maria Orengo12Matteo Bauckneht13Silvia Morbelli14Silvia Ravera15Gianmario Sambuceti16Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), 20054 Milan, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyDepartment of Biomedical Sciences, University of Padova, 35131 Padua, ItalyInstitute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), 20054 Milan, ItalyDepartment of Experimental Medicine, Human Anatomy, University of Genoa, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyDepartment of Experimental Medicine, Human Anatomy, University of Genoa, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyISBE. IT, Centre of Systems Biology, 20126 Milan, ItalyInstitute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), 20054 Milan, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyDepartment of Experimental Medicine, Human Anatomy, University of Genoa, 16132 Genova, ItalyIRCCS Ospedale Policlinico San Martino, 16132 Genova, ItalyCancer utilization of large glutamine equivalents contributes to diverging glucose-6-P flux toward the pentose phosphate shunt (PPP) to feed the building blocks and the antioxidant responses of rapidly proliferating cells. In addition to the well-acknowledged cytosolic pathway, cancer cells also run a largely independent PPP, triggered by hexose-6P-dehydrogenase within the endoplasmic reticulum (ER), whose activity is mandatory for the integrity of ER–mitochondria networking. To verify whether this reticular metabolism is dependent on glutamine levels, we complemented the metabolomic characterization of intermediates of the glucose metabolism and tricarboxylic acid cycle with the estimation of proliferating activity, energy metabolism, redox damage, and mitochondrial function in two breast cancer cell lines. ER-PPP activity and its determinants were estimated by the ER accumulation of glucose analogs. Glutamine shortage decreased the proliferation rate despite increased ATP and NADH levels. It depleted NADPH reductive power and increased malondialdehyde content despite a marked increase in glucose-6P-dehydrogenase. This paradox was explained by the deceleration of ER-PPP favored by the decrease in hexose-6P-dehydrogenase expression coupled with the opposite response of its competitor enzyme glucose-6P-phosphatase. The decreased ER-PPP activity eventually hampered mitochondrial function and calcium exchanges. These data configure the ER-PPP as a powerful, unrecognized regulator of cancer cell metabolism and proliferation.https://www.mdpi.com/2076-3921/12/1/43glutamine metabolismbreast cancerpentose phosphate pathwayredox balancehexose-6-phosphate-dehydrogenase<sup>18</sup>F-fluoro-deoxy-glucose |
| spellingShingle | Cecilia Marini Vanessa Cossu Sonia Carta Elisa Greotti Daniela Gaglio Nadia Bertola Sabrina Chiesa Silvia Bruno Francesca Vitale Marcella Bonanomi Danilo Porro Mattia Riondato Anna Maria Orengo Matteo Bauckneht Silvia Morbelli Silvia Ravera Gianmario Sambuceti Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells Antioxidants glutamine metabolism breast cancer pentose phosphate pathway redox balance hexose-6-phosphate-dehydrogenase <sup>18</sup>F-fluoro-deoxy-glucose |
| title | Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells |
| title_full | Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells |
| title_fullStr | Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells |
| title_full_unstemmed | Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells |
| title_short | Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells |
| title_sort | fundamental role of pentose phosphate pathway within the endoplasmic reticulum in glutamine addiction of triple negative breast cancer cells |
| topic | glutamine metabolism breast cancer pentose phosphate pathway redox balance hexose-6-phosphate-dehydrogenase <sup>18</sup>F-fluoro-deoxy-glucose |
| url | https://www.mdpi.com/2076-3921/12/1/43 |
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