Recent studies have unveiled a diverse mechanisms for cancer cells to achieve metabolic reprogramming. Aldolase catalyzes the cleavage of fructose-1,6-bis-phosphate (FBP) to generate dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP) in glycolysis, as well as the reverse reaction of DHAP and GAP to FBP in gluconeogenesis.  

Aldolase B (Aldob) is abundantly expressed in the liver, small intestine, and kidney. Previous studies have found that Aldob is down-regulated in liver cancer tissues and its expression is reversely correlated to clinical prognosis for liver cancer patients. However, the molecular mechanisms and clinical significance of Aldob downregulation in hepatocellular carcinoma (HCC) remain to be defined.  

In a study published in Nature Cancer, Dr. YIN Huiyong's group at the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) discovered a novel mechanism by which Aldob regulates liver cancer metabolic reprogramming. 

The researchers started out from gene expression microarray analysis of paired human HCC tissues. They found that the expression of Aldob was significantly downregulated, whereas glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), was significantly upregulated in tumor tissues compared to peripheral normal tissue. A low expression of Aldob and high G6PD expression was positively associated with short overall survival and poor prognosis for HCC patients.  

A multivariate analysis demonstrated that Aldob is an independent risk factor for HCC. Using N-Nitrosodiethylamine (DEN)-induced HCC mouse model, the researchers found that global or liver specific knockout (KO) of Aldob promotes hepatocellular carcinogenesis through enhancing G6PD activity to increase the metabolic flux to PPP, while re-expression of Aldob in liver-specific Aldob KO mice suppresses HCC. Consistently, pharmacological inhibition or genetic knocking down G6PD attenuates the tumor formation. All these in vivo data suggested that Aldob opposes HCC through regulation of G6PD and PPP.  

Besides, they demonstrated that in normal liver cells, Aldob interacts with G6PD to inhibit its activity, and the presence of Aldob enhances the inhibitory effect of tumor suppressor p53 on G6PD through a protein complex containing Aldob, G6PD and p53 to regulate cell metabolism. In cancer cells, however, Aldob downregulation releases G6PD activity and attenuates the inhibitory effect of p53 on G6PD, leading to the increased metabolism of PPP to meet the need for rapid growth of cancer cells. 

This study defined a new molecular mechanism for cancer cell metabolic reprogramming, i.e., the interaction of metabolic enzymes Aldob and G6PD regulates cell metabolism in glycolysis and pentose phosphate pathways, whereas the loss of Aldob in tumor cells leads to rewire metabolic pathways to favor tumor growth. It showed a new non-enzymatic function of Aldob, highlighting a clinical significance in diagnosis and treatment of liver cancer. 

Aldob inhibits liver cancer by directly interacting with G6PD and enhancing p53-mediated inhibition of G6PD. (Image by Prof. YIN Huiyong's Group)