Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an article presented in this issue of Molecular Pharmacology, Yacoub et al. (p. 589) examine the actions of 2-amino-N{4-5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-acetamide (OSU-03012) on both primary and glioblastoma cell lines. The authors found that OSU-03012 could induce tumor cell death by itself but also acted as a strong sensitizing agent to radiotherapy-induced cell death. Glioblastoma cells were also more sensitive to this compound than nontransformed astrocytes. Radiation-induced cell death was refractory to small interfering RNA-directed inhibition of PDK1 but not OSU-03012. These results indicate that OSU-03012, which has been thought to primarily mediate antitumor effects via the inhibition of PDK1, has actions independent of PDK1. Furthermore, the authors demonstrated that the effects of OSU-03012 were independent of ERB-B1-vIII and PTEN expression. These are important findings because they start to identify a new mechanism to sensitize glioblastoma cells and also suggest that OSU-03012 could be combined with existing inhibitors to further sensitize tumor cells. In glioblastoma cells, OSU-03012 seemed to induce apoptosis via endoplasmic reticulum stress-induced PERK-dependent signaling. OSU-03012-induced death of the glioblastoma was only weakly suppressed by the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp, suggesting that OSU-03012-induced cell death was largely caspase-independent. Overall, these are exciting results and suggest that new more effective treatment options may be obtainable for people suffering from these deadly tumors.
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PMID:OSU-03012 in the treatment of glioblastoma. 1667 57

Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROSLow cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.
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PMID:ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells. 2941 12

Corticosteroid associated osteonecrosis is bone death resulting from the use of chronic glucocorticoids and most commonly affects the femoral head, although the bones such as around knee joint, wrist joint and ankle joint can be affected. The pathogenesis is likely multifactorial, with genetic and environmental factors playing a role. Epigenetics may be the mechanism by which environment exerts it effects. In spite of recent discoveries, the exact pathogenesis of corticosteroid associated osteonecrosis is unknown. Over the past few years, more miRNA's have been found to be associated with osteonecrosis. The older mechanisms such as a coagulopathy, abnormalities in apoptosis and lipid metabolism dysfunction are still believed to play a role. The role of inflammatory pathways including the PDK1/AKT/mTOR signaling pathway, the PERK and Parkin pathways have been increasingly recognized as playing a mechanistic role. Histological damage to the joint can occur before the presence of symptoms. The most common symptoms are pain and an inability to bear weight. Differential diagnosis includes infection, bone marrow edema syndrome or subchondral fracture. Early detection is important for successful management of the condition. MRI is the best radiologic technique to diagnosis femoral head osteonecrosis. Multiple staging systems for osteonecrosis have been used over the years, including the Ficat and Arlet system and the Steinberg criteria. The later stages of these staging systems are irreversible. Both non-surgical (conservative) and surgical modes of therapy are used in the treatment of osteonecrosis.
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PMID:The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. 3230 11