Autor(es):
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
Data: 2023
Identificador Persistente: https://hdl.handle.net/10316/113819
Origem: Estudo Geral - Universidade de Coimbra
Projeto/bolsa:
info:eu-repo/grantAgreement/other/04539//other;
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/PT;
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/PT;
Assunto(s): Roy-Bz; PKCδ; anticancer agent; OXPHOS; glycolysis
Descrição
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.
