SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner

Abstract

The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination.

MUC16 promotes EOC proliferation by regulating GLUT1 expression

“…It is often observed GLUT1 abnormal expression in tumour cells promote the ‘Warburg effect’ 29 . GLUT1 provide promising targets for tumour targeting therapy 30 .…”

“…promote the 'Warburg effect'. 29 GLUT1 provide promising targets for tumour targeting therapy. 30 In this paper, our results show that the expression of GLUT1 was significantly promoted by MUC16.…”

Monocarboxylate Transporters 1 and 4 and MTCO1 in Gastric Cancer

“…Lactate is not only a waste for tumors; cancer cells also become more aggressive and resistant to therapy by acidifying their microenvironment. Low pH and lactate enable cancer cells to migrate, invade, promote angiogenesis, immune escape, and radioresistance [ 20 , 21 , 22 ]. The MCT family includes 14 members, among which MCT1-4 are catalyzing the proton-linked transport of pyruvate, lactate, and ketone bodies across the cell membrane [ 23 ].…”

Downregulation of GLUT3 impairs STYK1/NOK‑mediated metabolic reprogramming and proliferation in NIH‑3T3 cells

“…Notably, a considerable number of studies have suggested that STYK1/NOK can activate various proliferation-related signaling pathways or molecules (31)(32)(33). A number of the signaling pathways have been reported to strictly regulate the expression and subcellular distribution of GLUTs, for instance, PI3K/Akt/mTOR, hypoxia-inducible factor-1, c-myc and tumor suppressor protein p53 (19,(34)(35)(36), which provides clues for the further exploration of the upstream molecular mechanism of GLUT3 in STYK1/NOK-overexpressing cells. This is the field of research that will be the focus of our work and studies in the future.…”