Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin

Abstract

Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1-dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth.

Targeting the ROS/PI3K/AKT/HIF‐1α/HK2 axis of breast cancer cells: Combined administration of Polydatin and 2‐Deoxy‐d‐glucose

“…37,38 Therefore, correcting the level of glycolysis of malignant cancer cells is one of the emerging research hotspots in cancer chemotherapy. 37,38 Therefore, correcting the level of glycolysis of malignant cancer cells is one of the emerging research hotspots in cancer chemotherapy.…”

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

“…For example, hexokinase-2 (which is expressed in hepatocellular carcinoma, HCC, but not in normal hepatocytes) depletion sensitizes HCC cells to metformin. 54 In some special cases, loss-of-function mutation of OXPHOS-relevant genes can be oncogenic. Thus, hereditary leiomyomatosis renal cell carcinoma is characterized by fumarate hydratase nullizyogosity.…”

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2

“…For example, deletion of hepatic HK2 reduces the tumor incidence in a mouse model of hepatocarcinogenesis and HK2 knockdown inhibits tumorigenesis and increases cell death in vitro. 31 Due to the extremely polar active site of HK2 and the complexity of its protein functions, a limited number of HK2 small-molecule inhibitors of HK2 have been discovered. 40 In this study, we identify IKA as a HK2-selective small-molecule inhibitor for potential PDAC treatment or for use in combination with the first-line chemotherapeutic drugs.…”

“…In liver cancer, HK2 knockdown reduces glycolytic flux, and elevates serine uptake and glycine secretion; mechanistically, HK2 silencing in combination with metformin inhibit mTORC1 activity by increasing the expression of REDD1, which inhibits mTORC1 by activating TSC2. 31 In a mouse model of non-small cell lung cancer, glutamine-derived carbon incorporation into TCA cycle intermediates is reduced following Hk2 deletion. 33 Therefore, F I G U R E 6 The HK2-independent antitumor roles of Ikarugamycin.…”

“…30 HK2 is extensively implicated in tumor initiation and metastatic processes, and systemic deletion of HK2 exhibits remarkable antitumor effects. [31][32][33] Since HK2 is highly expressed in cancer cells, whereas in most adult tissues the predominant isoforms used are HK1, HK4 and to a lesser extent HK2, and HK3, therapeutic target of HK2 may allow for preferential killing of cancer cells without overt side effects. Several inhibitors of HK2 are amenable to antitumor therapy, such as 2-deoxy-D-glucose (2-DG), 34,35 3-bromopyruvate, 36 and Metformin.…”