The Promoting Role of HK II in Tumor Development and the Research Progress of Its Inhibitors

Abstract

Increased glycolysis is a key characteristic of malignant cells that contributes to their high proliferation rates and ability to develop drug resistance. The glycolysis rate-limiting enzyme hexokinase II (HK II) is overexpressed in most tumor cells and significantly affects tumor development. This paper examines the structure of HK II and the specific biological factors that influence its role in tumor development, as well as the potential of HK II inhibitors in antitumor therapy. Furthermore, we identify and discuss the inhibitors of HK II that have been reported in the literature.

Keywords: Warburg effect; antitumor; glycolysis; hexokinase II; inhibitors.

Figure 1

The structure of HK II (2NZT, PDB). HKⅡconsists of N- and C-terminal halves, and they are joined by α13. Each half also comprises large and small domains.

Figure 2

HK II during glycolysis. ADP and PI in the cytoplasm are transported into the mitochondrial matrix through the mitochondrial inner membrane via the AAC protein. They participate in the TCA cycle. The ATP produced is transported from the mitochondrial matrix to the intermembrane space through the AAC protein and participates in the process of glucose conversion to G6P mediated by HK II. The lactate produced is transported out of the cell through transport proteins on the cell membrane. AAC, mitochondrial ADP/ATP carrier; m-state, matrix-open state, the AAC protein transports ADP into the mitochondrial matrix, with the structure of the AAC protein referred to as the m-state during this process; c-state, cytoplasmic-open state, the AAC protein transports ADP into the mitochondrial matrix, with the structure of the AAC protein referred to as the c-state during this process; TCA, tricarboxylic acid cycle; VDAC, voltage-dependent anion-selective channel; HK II, hexokinase II; G6P: glucose 6-phosphate; F6P, fructose 6-phosphate; NDA+, nicotinamide adenine dinucleotide; NDAH, nicotinamide adenine dinucleotide (prototype).

Figure 3

Proteins and signaling pathways that cause HK II up-regulation. ErbB2, tyrosine kinase receptor 2; HectH9, an enzyme belonging to the HECT (Homologous to the E6-AP Carboxyl Terminus) protein family; TRIM59, tripartite motif-containing protein 59; PTEN, phosphatase and tensin homolog; AKT, protein Kinase B; BACH1, BTB and CNC homology 1; Nrf2, nuclear factor erythroid 2-related factor 2; PIM2, pre-B lymphoma virus insert site 2; MAPK, mitogen-activated protein kinase; STAT3, transcription 3; Wnt/β-catenin, canonical Wnt/β-catenin pathway; C-myc, cellular-myelocytomatosis viral oncogene; Cyclin D1, G1/S-specific cell cycle protein-D1; CREB, cAMP response-element binding protein; AR, androgen receptor; HIF-1α, hypoxia inducible factor 1 subunit alpha Gen; MZF1, myeloid zinc finger protein; SIRT6, a member of the histone deacetylase family; IL-1β, Interleukin-1β; , cicroRNA; , miRNA; , phosphorylation; , ubiquitination; , active.

Figure 4

Factors that contribute to the downward revision of HK II. Snail, snail family transcriptional repressor 1 gene; CREB, cyclic-AMP response-binding protein; KCNQ1OT1, a long non-coding RNA; IL13Rα1, interleukin-13 receptor subunit alpha-1.

Figure 5

Summary of various biological factors that impact HK II expression. , protein; , cicro RNA; , miRNA.

Figure 6

The mechanism by which HK II promotes drug resistance. After binding with VDAC, BCL-2 and/or HKII inhibit the release of cytochrome c from VDAC (left); when BAX and tBID are in the outer mitochondrial membrane, tBID binds to BAX/BAK, promoting their oligomerization and the release of cyt c (medium); HK II and BCL-x_L reverse the translocation of tBID and BAX/BAK from the outer mitochondrial membrane to the cytoplasm (right). BCL-2, B-cell lymphoma-2; BAX/BAK, BCL2-Associated X/K; Tbid, Bcl-2/BH3-only protein; ×, means inhibit.

Figure 7

Commonly used HK II inhibition in recent studies.

Figure 8

N-(2,3,4-trihydroxybenzyl)arylhydrazide HK II inhibitors and their conformational relationships. The highlighted structure is the most active.