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Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents.

PURPOSE: Bax plays an important role in the regulation of apoptosis induced by chemotherapy and other stimuli. We therefore investigated the role of Bax in drug-induced apoptosis in human pancreatic cancer cells. METHOD: A tetracycline-inducible retroviral expression vector bearing the human bax-alpha gene was constructed. ASPC-1 cells were stably infected with this vector. The sensitivity of the transformed cell line to gemcitabine and 5-Fu was assessed. RESULTS: Western blots revealed that Bax expression was enhanced in these cells by the tetracycline analogue doxycycline. Enhanced express

Lipid-induced mTOR activation in rat skeletal muscle reversed by exercise and 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside.

The serine/threonine protein kinase, mammalian target of rapamycin (mTOR) is regulated by insulin and nutrient availability and has been proposed to play a central role as a nutrient sensor in skeletal muscle. mTOR associates with its binding partners, raptor and rictor, to form two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) respectively. We have investigated the assembly of mTORC1/2 and the activation of their downstream substrates (i.e. Akt, S6K1) in response to known effectors of mTOR, excess lipid availability and AMP-activated pro

Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells.

Resveratrol is one of the most extensively studied cancer chemopreventive agents; however, its mechanisms of action are not completely understood. Here, we observed that resveratrol induces S phase arrest via Tyr15 phosphorylation of Cdc2 in human ovarian carcinoma Ovcar-3 cells. Overexpression of Cdc2AF, a mutant resistant to Thr14 and Tyr15 phosphorylation, ablated resveratrol-induced S phase arrest. Further upstream, we observed that resveratrol causes phosphorylation of cell division cycle 25C (Cdc25C) tyrosine phosphatase via the activation of checkpoint kinases Chk1 and Chk2, which in tu

A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers.

Macroautophagy/autophagy plays a critical role in the pathogenesis of various human diseases including neurodegenerative disorders such as Parkinson disease (PD) and Huntington disease (HD). Chemical autophagy inducers are expected to serve as disease-modifying agents by eliminating cytotoxic/damaged proteins. Although many autophagy inducers have been identified, their precise molecular mechanisms are not fully understood because of the complicated crosstalk among signaling pathways. To address this issue, we performed several chemical genomic analyses enabling us to comprehend the dominancy

κ-opioid receptor activation protects against myocardial ischemia-reperfusion injury via AMPK/Akt/eNOS signaling activation.

This study aims to investigate the effect of κ-opioid receptor activation on myocardial ischemia and reperfusion(I/R) injury and elucidate the underlying mechanisms. Myocardial I/R rat model and simulated I/R cardiomyocytes model were established. In vivo study showed that U50,488 H improved cardiac function, reduced myocardial infarct size and serum cTnT significantly. The effect of U50,488 H was abolished by nor-BNI(a κ-opioid receptor antagonist), Compound C(an AMPK inhibitor), Akt inhibitor and L-NAME(an eNOS inhibitor). AICAR, an AMPK activator, mimicked the effect of U50,488 H. U50,488 H

AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma.

BACKGROUND: Occupational asthma is characterized by airway inflammation and hyperresponsiveness associated with increased vascular permeability. AMP-activated protein kinase (AMPK) has been suggested to be a novel signaling molecule modulating inflammatory responses. OBJECTIVE: We sought to evaluate the involvement of AMPK in pathogenesis of occupational asthma and more specifically investigate the effect and molecular mechanisms of AMPK activation in regulating vascular permeability. METHODS: The mechanisms of action and therapeutic potential of an AMPK activator, 5-aminoimidazole-4-carboxa

Combination therapy with 5-amino-4-imidazolecarboxamide riboside and arsenic trioxide in acute myeloid leukemia cells involving AMPK/TSC2/mTOR pathway.

The aim of this study was to demonstrate the effects of the AMP-activated protein kinase (AMPK) activator 5-amino-4-imidazolecarboxamide riboside (AICAR) in combination with arsenic trioxide (ATO) in acute myeloid leukemia cells and determine its mechanism of action. Cell lines were either exposed to each drug alone or both the drugs simultaneously. Cell proliferation, cell cycle and apoptosis were assessed. Combination index (CI) method was used to calculate the synergistic, additive, or antagonistic effects of these drugs. Western blot technique was used to study the signaling molecules in t

P7 peptides suppress the proliferation of K562 cells induced by basic fibroblast growth factor.

Although it has been known that basic fibroblast growth factor (bFGF) is involved in tumor progression, few studies addressed the role of bFGF in hematopoietic system malignancies including chronic myeloid leukemia (CML). An elevated level of bFGF was recently found in CML patients, and bFGF was considered to play an important role in stimulating the growth of leukemia cells. Suppression of the mitogenic activity of bFGF may contribute to CML therapy. We have previously obtained a novel bFGF-binding peptide (named P7) with strong inhibitory activity against bFGF-induced cell proliferation. In

Whole body glucoregulation and tissue-specific glucose uptake in a novel Akt substrate of 160 kDa knockout rat model.

Akt substrate of 160 kDa (also called AS160 or TBC1D4) is a Rab GTPase activating protein and key regulator of insulin-stimulated glucose uptake which is expressed by multiple tissues, including skeletal muscle, white adipose tissue (WAT) and the heart. This study introduces a novel rat AS160-knockout (AS160-KO) model that was created using CRISPR/Cas9 technology. We compared male AS160-KO versus wildtype (WT) rats for numerous metabolism-related endpoints. Body mass, body composition, energy expenditure and physical activity did not differ between genotypes. Oral glucose intolerance was detec

AMP-activated Protein Kinase (AMPK) Control of mTORC1 Is p53- and TSC2-independent in Pemetrexed-treated Carcinoma Cells.

The key sensor of energy status in mammalian cells, AMP-activated protein kinase (AMPK), can also be activated by the AMP analog aminoimidazolecarboxamide nucleoside monophosphate (ZMP) generated directly from aminoimidazolecarboxamide ribonucleoside (AICAR) or from inhibition of purine synthesis by the antifolate pemetrexed (PTX), a drug used extensively in the treatment of lung cancers. Despite this common mechanism, signaling downstream of AMPK activated by PTX or AICAR differed. AICAR-activated AMPK inhibited mTORC1 both directly by phosphorylation of the mTORC1 subunit Raptor and indirect

Inhibition of the LKB1-AMPK pathway by the Epstein-Barr virus-encoded LMP1 promotes proliferation and transformation of human nasopharyngeal epithelial cells.

The association of Epstein-Barr virus (EBV) infection with the development of nasopharyngeal carcinoma (NPC) is well established. Latent membrane protein 1 (LMP1), the major oncogene encoded by EBV, is believed to play a crucial role in NPC pathogenesis by virtue of its ability to constitutively activate multiple cell signalling pathways. The LKB1-AMPK pathway is a master regulator of cellular metabolism that, via modulation of energy metabolism, has tumour suppressor activity. In this study we identify a novel ability of LMP1 to inhibit the LKB1-AMPK pathway through phosphorylation of LKB1 at

Paracetamol (N-acetyl-para-aminophenol) disrupts early embryogenesis by cell cycle inhibition.

STUDY QUESTION: Does paracetamol (N-acetyl-para-aminophenol (APAP) also known as acetaminophen) interfere with cell division and thereby disrupt pre-implantation embryonic development? SUMMARY ANSWER: Our findings suggest that APAP exposure inhibits cell cycling during pre-implantation development (PID) through the reduction of DNA synthesis, potentially resulting in early embryonic loss. WHAT IS KNOWN ALREADY: It is estimated that 10-40% of all human conceptions fail around the time of implantation. Genetic factors explain ∼50% of early embryonic loss, leaving a substantial portion of early

Regulation of ERK1/2 by ouabain and Na-K-ATPase-dependent energy utilization and AMPK activation in parotid acinar cells.

We previously found that the phosphorylation of ERK1/2 by submaximal concentrations of the muscarinic receptor ligand carbachol was potentiated in rat parotid acinar cells exposed to ouabain, a cardiac glycoside that inhibits the Na-K-ATPase. We now report that this signaling phenomenon involves the prevention of negative regulation of extracellular signal-regulated kinase-1/2 (ERK1/2) that is normally mediated by AMP-activated protein kinase (AMPK). Carbachol increases the turnover of the ATP-consuming Na-K-ATPase, reducing intracellular ATP and promoting the phosphorylation/activation of the

Iron deprivation in cancer--potential therapeutic implications.

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention i

Совпадение в полном тексте источника
… Importantly, iron is an essential cofactor for ribonucleotide reductase (RR), which catalyzes the rate-limiting step in DNA synthesis, the reduction of ribonucleotides to deoxyribonucleotides [ 11 ]. RR is comprised of two protein subunits. … Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. J. Biol. Chem. 1970;245:5228–5233. 12. Trinder D., Zak O., Aisen P. …

5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is a Th1-mediated inflammatory demyelinating disease of the CNS. AMP-activated protein kinase was reported recently to have anti-inflammatory activities by negatively regulating NF-kappaB signaling. In this study, we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), in active and passive EAE induced by active immunization with PLP(139-151) or MOG(35-55) and in adoptive transfer of PLP(139-151)-sensitize

Capsaicin induces apoptosis in human osteosarcoma cells through AMPK-dependent and AMPK-independent signaling pathways.

Recent studies have focused on the anti-tumor activity of capsaicin. However, the potential effects of capsaicin in osteosarcoma cells and the underlying mechanisms are not fully understood. In the current study, we observed that capsaicin-induced growth inhibition and apoptosis in cultured osteosarcoma cells (U2OS and MG63), which were associated with a significant AMP-activated protein kinase (AMPK) activation. AMPK inhibition by compound C or RNA interference suppressed capsaicin-induced cytotoxicity, while AMPK activators (AICAR and A769662) promoted osteosarcoma cell death. For the mechan

Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR.

The role of the AMP-activated kinase (AMPK) as a metabolic sensor in skeletal muscle has been far better characterized for glucose and fat metabolism than for protein metabolism. Therefore, the studies presented here were designed to examine the effects of 5-aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR)-induced AMPK signaling on effector mechanisms of mRNA translation and protein synthesis in cultures of C(2)C(12) myotubes. The findings show that, following AICAR (2 mM) treatment, AMPK phosphorylation was increased within 15 min and remained elevated throughout a 60-min time cou

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets.

The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL1

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… De novo nucleotide biosynthesis is governed by RNR, which catalyzes the pivotal conversion of ribonucleotides to deoxyribonucleotides as the rate‐determining step [ 113 ]. … In mammals, RNR is a tetrameric enzyme composed of two homotetrameric subunits, ribonucleotide reductase catalytic subunit M1 (RRM1) and ribonucleotide reductase catalytic subunit M2 (RRM2). …

Linkage of Metabolic Defects to Activated PIK3CA Alleles in Endothelial Cells Derived from Lymphatic Malformation.

BACKGROUND: Lymphatic endothelial cells (LECs) derived from lymphatic malformations (LMs) bear activated PIK3CA alleles yet display an inflammatory gene expression profile. A basis for the inflammatory phenotype was sought by screening for coexisting somatic mutations. METHODS AND RESULTS: Fourteen independent LEC populations bearing activated PIK3CA alleles were isolated from LM. These were characterized by the expression of growth and inflammatory genes (VEGFC, IL-6, COX-2, IL-8, HO-1, E-SEL) by qRT-PCR. Most commonly upregulated gene products were VEGFC, COX2, HO-1, and ANGPTL4. The specif