HK2 has also been reported to interact with the mammalian target of rapamycin complex 1 (mTORC1) by binding to its subunit, regulatory-associated protein of mTOR (Raptor) ( Figure 1) (Roberts et al., 2014). The interaction between HK2 and VDAC inhibits the release of intermembrane pro-apoptotic proteins, thereby protecting tumor cells from apoptosis ( Figure 1) (Linden et al., 1982). VDAC is a critical channel that regulates the release rate of mitochondrial intermembrane pro-apoptotic proteins, such as cytochrome c (Linden et al., 1982). HK2 binds to the mitochondrial membrane via its interaction with the outer membrane porin protein, voltage-dependent anion channel (VDAC) ( Figure 1). Hexokinase (HK2) is the first rate-limiting enzyme in glycolysis, which is highly expressed in tumor cells and acts as a potential target for cancer treatment (Chen J. We also described how they are regulated and their effects on chromatin modifications. In this review, we described the functions of metabolic enzymes and metabolites from glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on their non-metabolic functions.
These non-metabolic functions provide useful clues to develop more efficient anti-cancer therapy. Many metabolic enzymes and metabolites have non-metabolic functions in tumorigenesis, including regulation of chromatin modifications, gene transcription, DNA damage, etc. Recent studies show that tumor cells mainly use the tricarboxylic acid (TCA) cycle in the G1 phase and prefer glycolysis in the S phase (Liu et al., 2021), suggesting that both TCA cycle and glycolysis are important for tumor cells. However, the function of mitochondria in most tumor cells is intact. Initially, the mitochondria in tumor cells was thought to have defects, which makes them unable to perform oxidative phosphorylation and highly dependent on glycolysis (Dang and Semenza, 1999). Although aerobic glycolysis is a less efficient way to produce energy (2 ATP/glucose), it helps accumulate a large amount of metabolite precursors for biosynthesis of macromolecules, i.e., nucleic acids, fatty acids, and amino acids (Hanahan and Weinberg, 2011). The extensive studied metabolic reprogram is aerobic glycolysis, also known as the “Warburg effect.” That is, cancer cells preferentially convert pyruvate, the end product of glycolysis into lactate instead of transporting pyruvate into the mitochondria for oxidative phosphorylation. This metabolic reprogram enables cells to synthesize a large amount of precursors for biomacromolecule synthesis (Pavlova and Thompson, 2016).
Tumor cells need to change their metabolism to support their demands for rapid growth and proliferation, so called metabolism reprogram (Pavlova and Thompson, 2016).
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