SLMP53-1 inhibits tumor cell growth through regulation of glucose metabolism and angiogenesis in a P53-dependent manner

The Warburg effect is an emerging hallmark of cancer, which has p53 as its major regulator. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) as a new p53-activating agent with in vitro and in vivo antitumor activity. Herein, we investigated the molecular events underlying the antitumor activity of SLMP53-1 in colon cancer by analyzing its effect on glucose metabolism, angiogenesis and migration.

In colon HCT116 cancer cells, SLMP53-1 inhibited glycolysis through reduction of GLUT1, hexokinase-2, and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 protein levels, also depleting the lactate export in colon cancer cells. Conversely, it enhanced mitochondrial oxidative phosphorylation (OXPHOS), upregulating the synthesis of cytochrome-c oxidase 2 and cytochrome-c oxidase subunit 4. SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 levels, which corroborated an inhibition of extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition (EMT). Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor protein levels. In tumor tissues of xenograft mouse models carrying p53^+/+- and p53^-/--HCT116 cells treated with SLMP53-1 or vehicle obtained in our previous work, the levels of molecular markers of glycolysis, OXPHOS, angiogenesis and migration were evaluated, confirming the in vitro results and unveiling that SLMP53-1 effect is p53-dependent in tumor tissues of colon cancer xenografts. SLMP53-1 exhibited synergistic cytotoxicity with the metabolic regulator dichloroacetic acid.

These data reinforce the promising application of SLMP53-1 in cancer therapy by targeting p53-mediated pathways of growth and dissemination.