Counteracting Colon Cancer by Inhibiting Mitochondrial Respiration and Glycolysis with a Selective PKCδ Activator

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5710
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Acidification; Adenosine triphosphate; anticancer agent; Antitumor activity; Apoptosis; Bioenergetics; Cancer therapies; Cell Line, Tumor; Colon cancer; Colonic Neoplasms - pathology; Colorectal cancer; Cytochrome; Cytochrome c; Cytochrome oxidase; Cytochrome-c oxidase; Development and progression; Dextrose; Electron transfer; Electron transport; Electron Transport Complex IV - metabolism; Glucose; Glucose - metabolism; Glucose transporter; Glycolysis; Health aspects; Hexokinase; Humans; Instrument industry; International economic relations; Kinases; Metabolism; Mitochondria; Oxidase; OXPHOS; p53 Protein; Pharmaceutical industry; Physiological aspects; PKCδ; Proteins; Respiration; Roy-Bz; Tumor proteins; Tumors; Xenografts; Xenotransplantation; United States; Honduras; Portugal; Roy-Bz; OXPHOS; PKCδ; anticancer agent; glycolysis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24065710

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 7 -acetoxy-6 -benzoyloxy-12- -benzoylroyleanone (Roy-Bz) as a PKCδ-selective activator with potent anti-proliferative activity in colon cancer by stimulating a PKCδ-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 oxidase subunit 4 (COX4), voltage-dependent anion channel (VDAC) and mitochondrial import receptor subunit TOM20 homolog (TOM20), and upregulation of synthesis of cytochrome 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 -induced glycolysis and apoptosis regulator (TIGAR) protein levels. These results were further corroborated in tumor xenografts of colon cancer. Altogether, using a PKCδ-selective activator, this work evidenced a potential dual role of PKCδ 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.