The regulatory and synergistic effects of FBP2 and HKDC1 on glucose metabolism and malignant progression in gastric cancer

Fructose-1,6-bisphosphatase (FBPase) serves as the rate-limiting enzyme in gluconeogenesis and can be categorized into two subtypes: FBP1 and FBP2. FBP1 has been reported to exhibit reduced expression and impaired function in various malignant tumors. However, there is limited research investigating the role of FBP2 in tumorigenesis. Our results showed that the expression level of FBP2 in gastric cancer (GC) tissues was reduced compared to that in adjacent non-tumor tissues. Low FBP2 expression was correlated with adverse clinicopathological characteristics and unfavorable prognosis. Overexpression of FBP2 in GC cells resulted in a decreased expression level of hypoxia inducible factor-1α (HIF-1α), enhanced oxidative phosphorylation, and a modest reduction in glycolytic activity. Notably, the FBP2 has been shown to elevate the expression level of hexokinase domain-containing protein-1 (HKDC1). Both cellular and animal studies demonstrated that the overexpression of FBP2 or the knockdown of HKDC1 could attenuate the malignant biological behavior of GC. Moreover, the synergistic effect of these two approaches exerted a more potent anti-tumor response. Overall, the synergistic effect of FBP2 and HKDC1 can suppress the progression of GC through the promotion of oxidative phosphorylation and inhibition of glycolysis. FBP2 and HKDC1 are anticipated to serve as novel molecular markers for the diagnosis, targeted therapy, and prognosis of GC.