A novel small molecule glycolysis inhibitor WZ35 exerts anti-cancer effect via metabolic reprogramming

Abstract

Background Liver cancer is the fifth leading cause of cancer death worldwide, but early diagnosis and treatment of liver cancer remains a clinical challenge. How to screen and diagnose liver cancer early and prolong the survival rate is still the focus of researchers. Methods Cell experiments were used to detect the effect of WZ35 on the colony formation ability and proliferation activity of hepatoma cells, nude mouse experiment to observe the in vivo anticancer activity and toxic side effects of WZ35; metabolomics analysis, glucose metabolism experiment and Seahorse analysis of liver cancer cells treated with WZ35; cell experiments combined with bioinformatics analysis to explore the mechanism of WZ35-mediated metabolic reprogramming to exert anticancer activity; tissue microarray and case analysis to evaluate the clinical significance of biomarkers for early diagnosis, treatment and prognosis evaluation of liver cancer. Results WZ35 inhibited the proliferation activity of various cell lines of liver cancer, and showed good therapeutic effect in nude mice model of hepatocellular carcinoma without obvious toxic and side effects; WZ35 inhibited the absorption of glucose in hepatoma cells, and the drug effect glycolysis, phosphorylation and purine metabolism are relatively seriously damaged; WZ35 mainly inhibits YAP from entering the nucleus as a transcription factor activator by activating oxidative stress in liver cancer cells, reducing the transcription of GLUT1, and finally reducing its GLUT1. Tissue microarray and case analysis showed that GLUT1 and YAP were highly expressed and correlated in liver cancer patients, and were associated with poor patient prognosis. The GLUT1-YAP risk model had a high score in predicting prognosis. Conclusion The study confirms that WZ35 is a small molecule glycolysis inhibitor, and through its properties, it mediates metabolic reprogramming dominated by impaired glycolysis, oxidative phosphorylation and purine metabolism to inhibit the proliferation activity of liver cancer cells. Our findings present novel insights into the pathology of liver cancer and potential targets for new therapeutic strategies. GLUT1-YAP has important reference significance for predicting the stages of disease progression in liver cancer patients and have the potential to serve as novel biomarkers for the diagnosis and treatment of liver cancer.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets

“…The SLC2As have a strong correlation with cancer patient survival. For instance, SLC2A1 was found to be deleterious in LIHC, LUAD, PAAD, and SARC, this finding was similar across many databases and the majority of prior research [ [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] ]. Also, we discovered that in LIHC and KIRC, improved OS was correlated with increased expression of SLC2A2.…”

Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP‐J/NRF2/FDX1 pathway

“…EF24 has been documented to significantly suppress the growth of various tumors such as breast cancer, 53 ovarian cancer, 54 cervical cancer, 55 and gastric cancer 56 . WZ35 has shown significant inhibitory effects on gastric cancer, 57 liver cancer, 58 and breast cancer 38 . GO‐Y030 exhibits remarkable inhibition against colon cancer, 59 DMC inhibits the proliferation of renal cancer, while MHMM41 impedes the growth of human lung cancer cells 60 .…”

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy

“…This inhibitory effect on autophagy of liver tumor cells is dependent on YAP1 ( 185 ). On the other hand, WZ35 reduces SLC2A1-mediated glycolysis by inhibiting YAP1, thus inhibiting the proliferation of liver tumor cells ( 186 ).…”

“…WZ35 is a new curcumin derivative, which shows anti-tumor activity in gastric tumor, breast tumor, colon tumor and prostate tumor (219)(220)(221)(222)(223). Recent studies have found that WZ35 has inhibitory activity in liver tumor, and its mechanism is related to the down-regulation of YAP1 expression (185,186). On the one hand, WZ35 inhibits the growth of liver tumor cells by downregulating autophagy controlled through YAP1.…”