Hepatocellular carcinoma (HCC) is the 10th most common cancer but the fourth leading cause of cancer-related death in the United States. To date, the only FDA-approved molecular therapy, sorafenib, has not been effective. This grant is aimed at determining the role of hexokinase 2 (HK2) in HCC development and progression, and whether or not HK2 is a viable drug target for HCC treatment. Normal healthy adult hepatocytes express glucokinase, a low affinity hexokinase. However, during pathological transition to cirrhosis and HCC, transformed hepatocytes silence glucokinase and induce HK2. We have shown this isoform transition in both human HCC cell lines and in a tumor microarray of 312 samples from 153 patients. This transition also represents a more general metabolic alteration whereby cancer cells increase glucose utilization and lactate secretion despite ample oxygen being present, also known as the Warburg Effect. HK2 is a ?mitochondrial? hexokinase, meaning it is capable of binding to the voltage dependent ion channel on the mitochondria, and we have data suggesting this interaction is essential for both tumorigenesis and efficient glucose utilization. Part of this grant will determine by what mechanism the mitochondrial interaction of HK2 promotes tumorigenesis and more generally why mitochondrial binding is necessary for full glycolytic capacity. We have shown that knockdown of HK2 beyond 70% is lethal to HCC cells, and indeed another group has shown that having either HK1 or HK2 is essential for cancer cell viability using a CRISPR/Cas9 knockout screen. Since HCC cells only express HK2, we believe HK2 is an ideal drug target for HCC. We will determine the feasibility of this therapeutic strategy using established mouse models of HCC to determine the cell autonomous necessity of HK2 in HCC initiation and progression. We will emulate drug therapy by using a doxycycline-inducible shRNA targeting HK2 in human HCC cells following subcutaneous implantation in nude mice. We will also determine if targeting mitochondrial glutamine metabolism synergizes with HK2 inhibition. Preliminary data suggests that production of NADPH, an important electron source for fatty acid synthesis and redox balance in cancer cells, is completely dependent on malic enzyme 1 and glutamine metabolism in HCC cells. We will exploit this dependency with a glutaminase-1 inhibitor, BPTES, or a complex-1 inhibitor, metformin in concert with HK2 inhibition. HK2 deletion should prevent compensatory activation of the pentose phosphate pathway and compensatory flux of glycolytic pyruvate into the mitochondria for TCA-flux, creating synergism with BPTES or metformin.

Public Health Relevance

Hepatocellular carcinoma (HCC) is the 10th most common cancer but 4th leading cause of cancer-related death in the US, with a 5-year survival rate of 17%. The proposed research project will determine how cellular metabolism changes in HCC development and progression, and whether or not hexokinase 2 is a viable drug target for HCC treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA225058-04
Application #
10114122
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2018-02-16
Project End
2022-11-15
Budget Start
2021-02-16
Budget End
2022-02-15
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Pusec, Carolina M; De Jesus, Adam; Khan, Md Wasim et al. (2018) Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology :
DeWaal, Dannielle; Nogueira, Veronique; Terry, Alexander R et al. (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446