The Requirement of Hexokinase 2 in The Process of Tumorigenesis: Implications for Cancer Therapy
thesisposted on 28.06.2013, 00:00 by Krushna C. Patra
One of the discernable biochemical changes occurring in cancer is the accelerated glucose metabolism. The expression level of the hexokinase 2 (HK2) catalyzing the first committed step in glucose metabolism is elevated in tumors. Analysis of human liver, lung and breast cancer tissue arrays by IHC showed that HK2 is detected exclusively in tumor lesions and that its expression level is positively correlated with the pathologic stage. Although the expression of HK2 is undetectable in most of the normal tissues, its expression is elevated in corresponding tumor tissues isolated from various mouse models of cancer. To understand the role of HK2 in tumor initiation and maintenance we employed HK2 conditional knockout (KO) mice. Deletion of HK2 significantly reduced the anchorage-independent growth of Ras transformed MEFs derived from these mice. HK2 ablation, through expression of shRNA, affected the anchorage-independent and xenograft growth of human liver, lung and breast cancer cells. Tumor onset/burden was significantly attenuated with genetic ablation of HK2 in MMTV-Neu and K-rasLSL mouse model of breast and lung cancer. In addition, cell lines derived from mammary gland tumors are dependent on HK2 for their ability to form tumors in an orthotropic transplantation model. Moreover, using K-rasLA2 mouse model of lung cancer, we showed that systemic whole body conditional deletion HK2 after tumor onset impairs tumor progression. Interestingly, systemic HK2 deletion is well tolerated and shows no overt phenotype in the mice. Metabolomic analyses of tumor cells derived from HK2 conditional KO mice showed that many anabolic pathways such as ribonucleic acid and TCA cycle are regulated by HK2. This may explain, at least in part, the impaired proliferation and anchorage-independent growth and tumor formation induced by HK2 deletion. In summary, our results provided a proof of concept that targeting HK2 could be therapeutic for cancer, without exerting adverse physiological consequences.