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Therefore, several efforts have been developed to find improved therapeutic approaches targeting cancer cell metabolism. Recently, we identified the 7\u03b1-acetoxy-6\u03b2-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz) as a PKC\u03b4-selective activator with potent anti-proliferative activity in colon cancer by stimulating a PKC\u03b4-dependent mitochondrial apoptotic pathway. Herein, we investigated whether the antitumor activity of Roy-Bz, in colon cancer, could be related to glucose metabolism interference. The results showed that Roy-Bz decreased the mitochondrial respiration in human colon HCT116 cancer cells, by reducing electron transfer chain complexes I\/III. Consistently, this effect was associated with downregulation of the mitochondrial markers cytochrome c oxidase subunit 4 (COX4), voltage-dependent anion channel (VDAC) and mitochondrial import receptor subunit TOM20 homolog (TOM20), and upregulation of synthesis of cytochrome c oxidase 2 (SCO2). Roy-Bz also dropped glycolysis, decreasing the expression of critical glycolytic markers directly implicated in glucose metabolism such as glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4), and increasing TP53-induced glycolysis and apoptosis regulator (TIGAR) protein levels. These results were further corroborated in tumor xenografts of colon cancer. Altogether, using a PKC\u03b4-selective activator, this work evidenced a potential dual role of PKC\u03b4 in tumor cell metabolism, resulting from the inhibition of both mitochondrial respiration and glycolysis. Additionally, it reinforces the antitumor therapeutic potential of Roy-Bz in colon cancer by targeting glucose metabolism.<\/jats:p>","DOI":"10.3390\/ijms24065710","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T03:33:57Z","timestamp":1679024037000},"page":"5710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Counteracting Colon Cancer by Inhibiting Mitochondrial Respiration and Glycolysis with a Selective PKC\u03b4 Activator"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-2329","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Bessa","sequence":"first","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u1f79rio de Microbiologia, Departamento de Ci\u00eancias Biol\u1f79gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Joana B.","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u1f79rio de Microbiologia, Departamento de Ci\u00eancias Biol\u1f79gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Matilde","family":"Barros","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u1f79rio de Microbiologia, Departamento de Ci\u00eancias Biol\u1f79gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9045-7287","authenticated-orcid":false,"given":"Vera M. S.","family":"Isca","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Research Center for Biosciences & Health Technologies, Universidade Lus\u00f3fona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal"},{"name":"Research Institute for Medicines (iMED.Ulisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7014-4614","authenticated-orcid":false,"given":"Vilma A.","family":"Sard\u00e3o","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Multidisciplinary Institute of Aging (MIA-Portugal), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paulo J.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1941-6634","authenticated-orcid":false,"given":"Raquel L.","family":"Bernardino","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Research, UMIB\u2014Unit for Multidisciplinary Research in Biomedicine, ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4200-465 Porto, Portugal"}]},{"given":"Carina","family":"Herman-de-Sousa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7664-2075","authenticated-orcid":false,"given":"Maria Adelina","family":"Costa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"},{"name":"Departamento de Qu\u00edmica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-9189","authenticated-orcid":false,"given":"Paulo","family":"Correia-de-S\u00e1","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-783X","authenticated-orcid":false,"given":"Marco G.","family":"Alves","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Research, UMIB\u2014Unit for Multidisciplinary Research in Biomedicine, ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4200-465 Porto, Portugal"},{"name":"Laboratory of Physiology, Department of Immuno-Physiology and Pharmacology, ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-8343","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Rijo","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Research Center for Biosciences & Health Technologies, Universidade Lus\u00f3fona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal"},{"name":"Research Institute for Medicines (iMED.Ulisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-4939","authenticated-orcid":false,"given":"Luc\u00edlia","family":"Saraiva","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u1f79rio de Microbiologia, Departamento de Ci\u00eancias Biol\u1f79gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1002\/cncr.33587","article-title":"The ever-increasing importance of cancer as a leading cause of premature death worldwide","volume":"127","author":"Bray","year":"2021","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3389\/fonc.2018.00203","article-title":"Cancer Stem Cell Metabolism and Potential Therapeutic Targets","volume":"8","author":"Snyder","year":"2018","journal-title":"Front. 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