Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer

Abstract

Summary Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.

Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics

“…Instead, the expression of hexokinase 2 (HK2) was significantly up-regulated in HCC with a single lesion, but was kept unchanged in the HCC with multiple lesions. Recent studies have demonstrated that the HK2 could promote glycolysis in tumor cells but not in normal cells [60,61], and increase the tumor progression and aggressive behaviors in many cancers [62][63][64][65]. Palmieri et al have reported that the poor patient survival and the metastasis of breast cancer to the brain were significantly associated with high HK2 expression [66], and HK2 ablation even could inhibit the metastasis [61].…”

“…Recent studies have demonstrated that the HK2 could promote glycolysis in tumor cells but not in normal cells [60,61], and increase the tumor progression and aggressive behaviors in many cancers [62][63][64][65]. Palmieri et al have reported that the poor patient survival and the metastasis of breast cancer to the brain were significantly associated with high HK2 expression [66], and HK2 ablation even could inhibit the metastasis [61]. Therefore, the up-regulation of HK2 might associate with the larger tumor size and early tumor recurrence/metastasis features of the HCC with a single lesion as previously reported [19,67].…”

Metformin, cancer and glucose metabolism

“…This physical association facilitates glucose phosphorylation and protects cell from apoptosis (Pastorino & Hoek 2003). HK2 is highly expressed in lung and breast cancer and is required by proliferating cancer cells as demonstrated by the impairment of tumour progression following its downregulation (Fang et al 2012, Patra et al 2013. In the unbound state, HK2 exists in an open inactive structure (Fig.…”

Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways

“…An increase in glucose uptake and a shift toward aerobic glycolysis are commonly observed in several tumors. In breast cancers, mammary tumor-initiating cells (TICs) and undifferentiated basal-like mammary tumors (i.e., those mostly enriched in TICs) require glycolysis for self-renewal [36][37][38]. Strikingly, aerobic glycolysis is sufficient, at least in vitro, to induce malignant phenotypes in breast cancer cells [39].…”