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  • Silvestrol In addition recent research shows that HK contrib

    2022-06-27

    In addition, recent research shows that HK2 contributes to the inhibition of apoptosis through the suppression of the formation of mitochondrial permeability transition pores in association with voltage-dependent anion channel (VDAC) protein [11]. We also found that AKT2 mediates HK2 resistance to apoptosis induced by serum starvation. Since HK2 is closely related to the nutritional metabolism of tumor cells, we only tested serum starvation-induced apoptosis in the present study. In a future experiment, we will examine whether AKT2 mediates HK2 resistance to apoptosis induced by other factors. AKT has been well-characterized as a serine/threonine protein kinase that phosphorylates the RXRXX(S/T) signature sequence [24], and HK2 exhibits the typical AKT phosphorylation sequence, QHRARQKT473. Moreover, a study has confirmed that the total AKT can phosphorylate Thr-473 HK2 and increase the binding of mitochondria and HK2 to protect cardiomyocytes [25]; however, the authors did not determine which subtype of AKT plays a role in this process. In addition, in colon cancer cells, no studies to date have assessed whether AKT2 can phosphorylate Thr-473 of HK2. Indeed, although wild type HK2 was found to be phosphorylated by AKT2, the phosphorylation did not occur when threonine 473 in HK2 was mutated. We also investigated whether AKT2 affects p-STAT3, NF-κB, Bcl-2, Bcl-XL, HIF1α, MMP2, and MMP9 via the phosphorylation of the T473 site of HK2, which are important molecules closely related to cancer cell invasion, apoptosis, and metastasis. We found that AKT2 regulates NF-κB, HIF1α, MMP2, and MMP9 via the phosphorylation of the HK2 T473 site. A previous study showed that HK2 is a downstream target of HIF1α [30]. However, in our study, we found that HK2 is the upstream molecule of HIF1α. This inconsistency may indicate that there are interactions in complex cellular signaling pathways in different cancer cells. We also found that AKT2 does not regulate the level of p-STAT3, Bcl-2, and Bcl-XL protein Silvestrol via HK2. In addition, to gain insight into the specific role of the AKT2-HK2-NF-κB/HIF1α/MMP2/MMP9 axis in colon cancer, there is a need to investigate how HK2 could modulate the expression of MMP2/9, HIF-1a and NF-κB in the future.
    Conclusions
    Introduction It is usually accepted that ATP generation in endothelial cells occurs primarily via glycolysis with little dependence on oxidative phosphorylation in mitochondria. Therefore, the impact of mitochondrial dysregulation on endothelial homeostasis has been largely disregarded in relative studies. However, this view is challenged by recent studies which show that fatty acid oxidation in mitochondria is a major source for ATP generation [1]. In fact, mitochondria are centrally involved in maintaining endothelial homeostasis, contributing to vascular function [2], [3]. In response to cellular stress, mitochondrial dysfunction is tightly associated with calcium overload, endoplasmic reticulum stress (ER stress), oxidative stress and apoptosis in endothelial cells, contributing to endothelial dysfunction [4], [5]. Hexokinases (HKs) catalyze the first step of glycolysis, converting glucose to glucose-6-phosphate. Hexokinase-II (HK-II) is a predominant isoform in insulin-sensitive tissue and plays an important role not only in glucose metabolism but also in cell survival. HK-II exerts anti-cell death effect and this action is dependent on its subcellular distribution. HK-II binds to the outer mitochondrial membrane with the connection of voltage-dependent anion channel 1 (VDAC1), which interacts with the adenine nucleotide translocase (ANT), forming a contact site between the outer and inner membranes [6]. This connection ensures tight coupling of glucose phosphorylation in the cytosol and ATP generation in mitochondria through ADP/ATP exchange, which is responsible for the maintenance of cellular homeostasis. Mitochondrial HK-II reduces ROS production, prevents mitochondrial permeability transition pore (mPTP) opening and provides protection against apoptosis by antagonizing apoptotic proteins [7], [8], [9], conferring protection of cell survival. Although mitochondrial HK-II has been documented to confer protection in cardiomyocytes [10], the potential role of mitochondrial HK-II in the protection of endothelial cells is little known.