Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer.
Inflammation is a hallmark of several disease states ranging from neurodegeneration to sepsis but is also implicated in physiological processes like ageing. Non-resolving inflammation and prolonged neuroinflammation are unclear processes implicated in several conditions, including ageing. In this study we studied the long-term effects of endotoxemia, as systemic lipopolysaccharide (LPS) injection, focusing on the role of astrocyte activation and cytokine release in the brain of aged rats. A single dose of LPS (2 mg/kg) or 0.9% saline was injected intraperitoneally in aged rats. Levels of pro-inflammatory cytokines (TNFα and IL-1β) and NF-κB p65 activation were measured systemically and in hippocampal tissue. Astrocytes and cytokines release in the CNS were detected via double immunofluorescence staining at different time-points up to day 30. Serum levels of TNFα and IL-1β were significantly increased acutely after 30 minutes (p<0.001) and up to 6 hours (p<0.001) following LPS-injection. Centrally, LPS-treated rats showed up-regulated mRNA expression and protein levels of pro-inflammatory cytokines in the hippocampus. These changes associated with astrogliosis in the hippocampus dentate gyrus (DG), IL-1β immunoreactivity and elevated NF-κB p65 expression up to day 30 post LPS exposure. Overall, these data demonstrate that LPS induces prolonged neuroinflammation and astrocyte activation in the hippocampus of aged rats. Hippocampal NF-κB p65 and excessive astrocytes-derived IL-1β release may play a pivotal role in regulating long-lasting neuroinflammation.
Heat shock transcription factor 1 (HSF1) is the master regulator of the proteotoxic stress response, which plays a key role in breast cancer tumorigenesis. However, the mechanisms underlying regulation of HSF1 protein stability are still unclear. Here, we show that HSF1 protein stability is regulated by PIM2-mediated phosphorylation of HSF1 at Thr120, which disrupts the binding of HSF1 to the E3 ubiquitin ligase FBXW7. In addition, HSF1 Thr120 phosphorylation promoted proteostasis and carboplatin-induced autophagy. Interestingly, HSF1 Thr120 phosphorylation induced HSF1 binding to the PD-L1 promoter and enhanced PD-L1 expression. Furthermore, HSF1 Thr120 phosphorylation promoted breast cancer tumorigenesis in vitro and in vivo. PIM2, pThr120-HSF1, and PD-L1 expression positively correlated with each other in breast cancer tissues. Collectively, these findings identify PIM2-mediated HSF1 phosphorylation at Thr120 as an essential mechanism that regulates breast tumor growth and potential therapeutic target for breast cancer.Significance: These findings identify heat shock transcription factor 1 as a new substrate for PIM2 kinase and establish its role in breast tumor progression.
Solubilization locations play a critical role in developing advanced surfactants and improving solubilization power in micelle‐based applications. However, the current polarity‐based techniques for measuring solubilization locations could come to conflicting conclusions. The key challenge is the unpredictable polarities in the micellar microenvironment. Now, an approach that is independent of micellar polarities is used to measure solubilization locations by covalently linking tetraphenylethylene (TPE) to the alkyl chain end of cationic surfactants. The solubilization locations of solubilized acceptors in the TPE‐cored spherical micelles were accurately measured by calculating the Förster resonance energy transfer distance between anchored TPE donors and solubilized acceptors. Solubilization locations of solubilized substances in the micellar interior and at the micellar surface depend on their size and hydrophobicity, respectively.
Chlorosilanes are versatile reagents in organic synthesis and material science.Amild pathway is nowreported for the quantitative conversion of hydrosilanes to silyl chlorides under visible-light irradiation using neutral eosin Ya s ah ydrogen-atom-transfer photocatalyst and dichloromethane as ac hlorinating agent. Stepwise chlorination of di-and trihydrosilanes was achieved in ah ighly selective fashion assisted by continuous-flowm icro-tubing reactors.T he ability to access silyl radicals using photocatalytic SiÀHa ctivation promoted by eosin Yoffers new perspectives for the synthesis of valuable silicon reagents in aconvenient and green manner.
The aim of the present study was to identify the effect of canavanine on the imidazoline receptor because canavanine is a guanidinium derivative that has a similar structure to imidazoline receptor ligands. Transfected Chinese hamster ovary-K1 cells expressing imidazoline receptors (nischarin (NISCH)-CHO-K1 cells) were used to elucidate the direct effects of canavanine on imidazoline receptors. In addition, the imidazoline I3 receptor has been implicated in stimulation of insulin secretion from pancreatic β-cells. Wistar rats were used to investigate the effects of canavanine (0.1, 1 and 2.5 mg/kg, i.v.) on insulin secretion. In addition the a specific I3 receptor antagonist KU14R (4 or 8 mg/kg, i.v.) was used to block I3 receptors. Canavanine decreased blood glucose by increasing plasma insulin in rats. In addition, canavanine increased calcium influx into NISCH-CHO-K1 cells in a manner similar to agmatine, the endogenous ligand of imidazoline receptors. Moreover, KU12R dose-dependently attenuated canavanine-induced insulin secretion in HIT-T15 pancreatic β-cells and in the plasma of rats. The data suggest that canavanine is an agonist of I3 receptors both in vivo and in vitro. Thus, canavanine would be a useful tool in imidazoline receptor research.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.