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Title: | Counteracting Colon Cancer by Inhibiting Mitochondrial Respiration and Glycolysis with a Selective PKCδ Activator | Authors: | Bessa, Cláudia Loureiro, Joana B. Barros, Matilde Isca, Vera M. S. Sardão, Vilma A. Oliveira, Paulo J. Bernardino, Raquel L. Herman-de-Sousa, Carina Costa, Maria Adelina Correia-de-Sá, Paulo Alves, Marco G. Rijo, Patrícia Saraiva, Lucília |
Keywords: | Roy-Bz; PKCδ; anticancer agent; OXPHOS; glycolysis | Issue Date: | 2023 | Publisher: | MDPI | Project: | UID/QUI/50006/2020 UIDB/00215/2020 UIDP/00215/2020 LA/P/0064/2020 SFRH/BD/137671/2018 CENTRO-01-0246-FEDER-000010 2021.03439.CEECIND UIDB/04033/2020 UIDB/04539/2020 info:eu-repo/grantAgreement/UIDP/04539/2020 LA/P/0058/2020 info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04567/2020/PT info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/04567/2020/PT |
Serial title, monograph or event: | International Journal of Molecular Sciences | Volume: | 24 | Issue: | 6 | Abstract: | Metabolic reprogramming is a central hub in tumor development and progression. Therefore, several efforts have been developed to find improved therapeutic approaches targeting cancer cell metabolism. Recently, we identified the 7a-acetoxy-6b-benzoyloxy-12-O-benzoylroyleanone (Roy- Bz) as a PKC -selective activator with potent anti-proliferative activity in colon cancer by stimulating a PKC -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 -selective activator, this work evidenced a potential dual role of PKC 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. | URI: | https://hdl.handle.net/10316/113819 | ISSN: | 1422-0067 | DOI: | 10.3390/ijms24065710 | Rights: | openAccess |
Appears in Collections: | I&D CIBB - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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Counteracting-Colon-Cancer-by-Inhibiting-Mitochondrial-Respiration-and-Glycolysis-with-a-Selective-PKC-ActivatorInternational-Journal-of-Molecular-Sciences.pdf | 2.9 MB | Adobe PDF | View/Open |
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