Gene Summary

Gene:APRT; adenine phosphoribosyltransferase
Aliases: AMP, APRTD
Summary:Adenine phosphoribosyltransferase belongs to the purine/pyrimidine phosphoribosyltransferase family. A conserved feature of this gene is the distribution of CpG dinucleotides. This enzyme catalyzes the formation of AMP and inorganic pyrophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP). It also produces adenine as a by-product of the polyamine biosynthesis pathway. A homozygous deficiency in this enzyme causes 2,8-dihydroxyadenine urolithiasis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:adenine phosphoribosyltransferase
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cultured Cells
  • Chromosome 16
  • Restriction Mapping
  • Adenine Phosphoribosyltransferase
  • DNA Repair
  • Cell Line
  • Genetic Variation
  • Base Sequence
  • Amino Acid Sequence
  • Transfection
  • Alleles
  • Carcinogenicity Tests
  • Molecular Sequence Data
  • Ultraviolet Rays
  • Colonic Neoplasms
  • Two-Dimensional Difference Gel Electrophoresis
  • Chromosome 8
  • Colorectal Cancer
  • Cancer DNA
  • Mutagenesis
  • Mutation
  • Neurofibromatosis 1
  • Genetic Markers
  • Phenotype
  • Cell Differentiation
  • Loss of Heterozygosity
  • chromium hexavalent ion
  • Genome
  • Adenocarcinoma
  • Neoplastic Cell Transformation
  • Cesium Radioisotopes
  • alpha 1-Antitrypsin
  • Oxidative Stress
  • Signal Transduction
  • Skin Cancer
  • Hypoxanthine Phosphoribosyltransferase
  • Drug Resistance
  • Polymerase Chain Reaction
  • Gene Deletion
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: APRT (cancer-related)

Feng F, Wu J, Gao Z, et al.
Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships.
Medicine (Baltimore). 2017; 96(1):e5679 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC.The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA-DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co-regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA-DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA-TF regulation network.A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA-DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co-regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA-TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR-1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP-responsive element modulator (CREM) were the critical regulated TFs.Four up-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM.

Shabestari RM, Safa M, Alikarami F, et al.
CREB knockdown inhibits growth and induces apoptosis in human pre-B acute lymphoblastic leukemia cells through inhibition of prosurvival signals.
Biomed Pharmacother. 2017; 87:274-279 [PubMed] Related Publications
A majority of acute lymphoblastic leukemia patients overexpress CREB in the bone marrow. However, the functional significance of this up-regulation and the detailed molecular mechanism behind the regulatory effect of CREB on the growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells has not been elucidated. We demonstrated here that CREB knockdown induced apoptosis and impaired growth of BCP-ALL NALM-6 cells which was associated with caspase activation. The gene expression levels of prosurvival signals Bcl-2, Mcl-1, Bcl-xL, survivin and XIAP were down-regulated upon CREB suppression. These findings indicate a critical role for CREB in proliferation, survival, and apoptosis of BCP-ALL cells. The data also suggest that CREB could possibly serve as potential therapeutic target in BCP-ALL.

Laytragoon-Lewin N, Cederblad L, Andersson BÅ, et al.
Single-Nucleotide Polymorphisms and Cancer Risk, Tumor Recurrence, or Survival of Head and Neck Cancer Patients.
Oncology. 2017; 92(3):161-169 [PubMed] Related Publications
OBJECTIVE: This paper aims at studying the influence of single-nucleotide polymorphisms (SNPs) on cancer risk, tumor recurrence, and survival in head and neck (H&N) cancer patients.
METHODS: A total of 45 SNPs in 41 genes were investigated. A total of 174 Caucasian H&N cancer patients and 245 healthy blood donors were enrolled in the study.
RESULTS: Ten SNPs were associated with H&N cancer risk, but the identified SNPs differed among males and females. Some of the SNPs were related to immune response genes. The immune response gene SNPs were also related to survival. In particular, we noted that the tumor necrosis factor alpha (TNFα) rs1800629 could have an influence on cancer risk, tumor recurrence as well as survival.
CONCLUSION: Genetic variation of the TNFα rs1800629 might be useful as a biomarker in clinical decision-making since it was found to be related to cancer risk, tumor recurrence, and survival of H&N cancer patients.

Zhang N, Xie Y, Tai Y, et al.
Bufalin Inhibits hTERT Expression and Colorectal Cancer Cell Growth by Targeting CPSF4.
Cell Physiol Biochem. 2016; 40(6):1559-1569 [PubMed] Related Publications
BACKGROUND/AIMS: Bufalin can induce apoptosis in certain human cancer cell lines, but bufalin has not yet been thoroughly evaluated in colorectal cancer cells. Cleavage and polyadenylation specific factor 4 (CPSF4) and human telomerase reverse transcriptase (hTERT) play important roles in colorectal cancer growth. The aim of this study was to investigate the roles and interactions of bufalin, CPSF4 and hTERT and the effects of bufalin in human colorectal cancer.
METHODS: We treated LoVo and SW620 cells with bufalin to investigate the effect of bufalin on proliferation, apoptosis and migration. We verified the relationship between CPSF4 and hTERT using pulldown assays, luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays.
RESULTS: Bufalin inhibited the proliferation and migration of and induced apoptosis in LoVo and SW620 cells. We identified CPSF4 as an hTERT promoter-binding protein in colorectal cancer cells.
CONCLUSION: Our study identified bufalin as a potential small molecule inhibitor for cancer therapy.

Ritter DI, Roychowdhury S, Roy A, et al.
Somatic cancer variant curation and harmonization through consensus minimum variant level data.
Genome Med. 2016; 8(1):117 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice.
METHODS: We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD.
RESULTS: Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data.
CONCLUSIONS: We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice.

Yu Y, Hou L, Song H, et al.
Akt/AMPK/mTOR pathway was involved in the autophagy induced by vitamin E succinate in human gastric cancer SGC-7901 cells.
Mol Cell Biochem. 2017; 424(1-2):173-183 [PubMed] Related Publications
Vitamin E succinate (VES), a derivative of vitamin E, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing apoptotic cell death. The effects of VES on autophagy, an intricate programmed process which helps cells survive in some stressed situations by degrading some cytoplasmic material, are unclear. When human gastric cancer cells SCG-7901 were exposed to VES, both the level of microtubule-associated protein 1 light chain 3 and the yeast ATG6 homolog Beclin-1 increased, and related autophagy genes were activated, thereby suggesting that autophagy was induced by VES. We also observed that VES-induced autophagy was accompanied by the activation of AMP-activated protein kinases (AMPK). VES-induced autophagy decreased when AMPK was inhibited by using small interfering RNA (siRNA), thereby suggesting that VES-induced autophagy is mediated by AMPK. Moreover, further studies revealed that the decreased activity of mammalian target of rapamycin (mTOR) and its downstream targets P70S6K and 4EBP-1 were involved in VES-activated autophagy associated with AMPK activation. The experiments also showed that the activity of protein kinases B (Akt)-mTOR axis was inhibited by VES. VES-induced AMPK activation could be attenuated by Akt activation. Overall, our studies demonstrated that AMPK was involved in the VES-induced autophagy. Crosstalk exists between AMPK and the Akt/mTOR axis. The results elucidated the mechanism of VES-induced autophagy in human gastric cancer cells.

Wang Q, Wang Y, Xing Y, et al.
Physcion 8-O-β-glucopyranoside induces apoptosis, suppresses invasion and inhibits epithelial to mesenchymal transition of hepatocellular carcinoma HepG2 cells.
Biomed Pharmacother. 2016; 83:372-380 [PubMed] Related Publications
BACKGROUND: Aberrant increased expression of DNMT1 and resulting silence of tumor suppressor genes have been found in a variety of human malignancies and DNMT1 has been considered as a promising therapeutic target for cancer prevention and treatment. One of the main active ingredients of Rumex japonicus Houtt, physcion 8-O-β-glucopyranoside (PG), has been found to have antitumor activities.
MATERIALS AND METHODS: Human hepatocellular carcinoma (HCC) cell line HepG2 was examined. Cell proliferation was analyzed using MTT assay. The apoptosis, migration and invasion were determined by flow cytometry, wound healing and Transwell assay, respectively. The expression of signaling molecules were examined by RT-PCR and western blots.
RESULTS: Our results provide experimental evidence that PG inhibits growth and suppresses invasion of HCC cells by downregulating DNMT1 via ROS-dependent AMP-activated protein kinase (AMPK)-mediated modulation of transcription factor Sp1.
CONCLUSION: our results revealed for the first time that PG inhibits growth and suppresses invasion of HCC, highlighting the anti-tumor activities of PG against HCC. However, further studies, including clinical trials, are needed to fully evaluate PG as a novel therapeutic in cancer prevention and treatment.

Georg B, Falktoft B, Fahrenkrug J
PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells.
Neuropeptides. 2016; 60:83-89 [PubMed] Related Publications
The neuropeptide PACAP is expressed throughout the central and peripheral nervous system where it modulates diverse physiological functions including neuropeptide gene expression. We here report that in human neuroblastoma NB-1 cells PACAP transiently induces its own expression. Maximal PACAP mRNA expression was found after stimulation with PACAP for 3h. PACAP auto-regulation was found to be mediated by activation of PACAP specific PAC1Rs as PACAP had >100-fold higher efficacy than VIP, and the PAC1R selective agonist Maxadilan potently induced PACAP gene expression. Experiments with pharmacological kinase inhibitors revealed that both PKA and novel but not conventional PKC isozymes were involved in the PACAP auto-regulation. Inhibition of MAPK/ERK kinase (MEK) also impeded the induction, and we found that PKA, novel PKC and ERK acted in parallel and were thus not part of the same pathways. The expression of the transcription factor EGR1 previously ascribed as target of PACAP signalling was found to be transiently induced by PACAP and pharmacological inhibition of either PKC or MEK1/2 abolished PACAP mediated EGR1 induction. In contrast, inhibition of PKA mediated increased PACAP mediated EGR1 induction. Experiments using siRNA against EGR1 to lower the expression did however not affect the PACAP auto-regulation indicating that this immediate early gene product is not part of PACAP auto-regulation in NB-1 cells. We here reveal that in NB-1 neuroblastoma cells, PACAP induces its own expression by activation of PAC1R, and that the signalling is different from the PAC1R signalling mediating induction of VIP in the same cells. PACAP auto-regulation depends on parallel activation of PKA, novel PKC isoforms, and ERK, while EGR1 does not seem to be part of the PACAP auto-regulation.

Liu S, Shapiro JM, Saloustros E, Stratakis CA
Bone Abnormalities in Mice with Protein Kinase A (PKA) Defects Reveal a Role of Cyclic AMP Signaling in Bone Stromal Cell-Dependent Tumor Development.
Horm Metab Res. 2016; 48(11):714-725 [PubMed] Related Publications
Protein kinase A (PKA) is an important enzyme for all eukaryotic cells. PKA phosphorylates other proteins, thus, it is essential for the regulation of many diverse cellular functions, including cytoplasmic trafficking and signaling, organelle structure and mitochondrial oxidation, nuclear gene expression, the cell cycle, and cellular division. The PKA holoenzyme is composed of 2 regulatory and 2 catalytic subunits. Four regulatory (R1α, R1β, R2α, and R2β) and 4 catalytic subunits (Cα, Cβ, Cγ, and Prkx) have been identified, giving rise to mainly PKA-I (when the 2 regulatory subunits are either R1α or R1β), or PKA-II (when the 2 regulatory subunits are either R2α or R2β). Mutations in the PKA subunits can lead to altered total PKA activity or abnormal PKA-I to PKA-II ratio, leading to various abnormalities in both humans and mice. These effects can be tissue-specific. We studied the effect of PKA subunit defects on PKA activity and bone morphology of mice that were single or double heterozygous for null alleles of the various PKA subunit genes. Bone lesions including fibrous dysplasia, myxomas, osteo-sarcomas, -chondromas and -chondrosarcomas were found in these mice. Observational and molecular studies showed that these lesions were derived from bone stromal cells (BSCs). We conclude that haploinsufficiency for different PKA subunit genes affected bone lesion formation, new bone generation, organization, and mineralization in variable ways. This work identified a PKA subunit- and activity-dependent pathway of bone lesion formation from BSCs with important implications for understanding how cyclic AMP affects the skeleton and its tumorigenesis.

Dong YY, Zhuang YH, Cai WJ, et al.
The mitochondrion interfering compound NPC-26 exerts potent anti-pancreatic cancer cell activity in vitro and in vivo.
Tumour Biol. 2016; 37(11):15053-15063 [PubMed] Related Publications
The development of novel anti-pancreatic cancer agents is extremely important. Here, we investigated the anti-pancreatic cancer activity by NPC-26, a novel mitochondrion interfering compound. We showed that NPC-26 was anti-proliferative and cytotoxic to human pancreatic cancer cells, possibly via inducing caspase-9-dependent cell apoptosis. Pharmacological inhibition or shRNA-mediated silence of caspase-9 attenuated NPC-26-induced pancreatic cancer cell death and apoptosis. Further, NPC-26 treatment led to mitochondrial permeability transition pore (mPTP) opening in the cancer cells, which was evidenced by mitochondrial depolarization, ANT-1(adenine nucleotide translocator-1)-Cyp-D (cyclophilin-D) association and oxidative phosphorylation disturbance. mPTP blockers (cyclosporin and sanglifehrin A) or shRNA-mediated knockdown of key mPTP components (Cyp-D and ANT-1) dramatically attenuated NPC-26-induced pancreatic cancer cell apoptosis. Importantly, we showed that NPC-26, at a low concentration, potentiated gemcitabine-induced mPTP opening and subsequent pancreatic cancer cell apoptosis. In vivo, NPC-26 intraperitoneal injection significantly suppressed the growth of PANC-1 xenograft tumors in nude mice. Meanwhile, NPC-26 sensitized gemcitabine-mediated anti-pancreatic cancer activity in vivo. In summary, the results of this study suggest that NPC-26, alone or together with gemcitabine, potently inhibits pancreatic cancer cells possibly via disrupting mitochondrion.

Guzmán-Rodríguez JJ, López-Gómez R, Salgado-Garciglia R, et al.
The defensin from avocado (Persea americana var. drymifolia) PaDef induces apoptosis in the human breast cancer cell line MCF-7.
Biomed Pharmacother. 2016; 82:620-7 [PubMed] Related Publications
Antimicrobial peptides (AMPs) are cytotoxic to cancer cells; however, mainly the effects of AMPs from animals have been evaluated. In this work, we assessed the cytotoxicity of PaDef defensin from avocado (Persea americana var. drymifolia) on the MCF-7 cancer cell line (a breast cancer cell line) and evaluated its mechanism of action. PaDef inhibited the viability of MCF-7 cells in a concentration-dependent manner, with an IC50=141.62μg/ml. The viability of normal peripheral blood mononuclear cells was unaffected by this AMP. Additionally, PaDef induced apoptosis in MCF-7 cells in a time-dependent manner, but did not affect the membrane potential or calcium flow. In addition, PaDef IC50 induced the expression of cytochrome c, Apaf-1, and the caspase 7 and 9 genes. Likewise, this defensin induced the loss of mitochondrial Δψm and increased the phosphorylation of MAPK p38, which may lead to MCF-7 apoptosis by the intrinsic pathway. This is the first report of an avocado defensin inducing intrinsic apoptosis in cancer cells, which suggests that it could be a potential therapeutic molecule in the treatment of cancer.

Ciccarese C, Brunelli M, Montironi R, et al.
The prospect of precision therapy for renal cell carcinoma.
Cancer Treat Rev. 2016; 49:37-44 [PubMed] Related Publications
The therapeutic landscape of renal cell carcinoma (RCC) has greatly expanded in the last decade. From being a malignancy orphan of effective therapies, kidney cancer has become today a tumor with several treatment options. Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). In this complex scenario it is important to find prognostic and predictive factors that can help in decision making in the treatment of mRCC.

Gadducci A, Biglia N, Tana R, et al.
Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning.
Crit Rev Oncol Hematol. 2016; 105:73-83 [PubMed] Related Publications
Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers.

Elmaci İ, Altinoz MA
A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme.
Biochem Genet. 2016; 54(5):573-618 [PubMed] Related Publications
Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3β). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3β, between AMPK and GSK-3β and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

Papanastasiou L, Fountoulakis S, Voulgaris N, et al.
Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures.
Hormones (Athens). 2016 Jan-Mar; 15(1):129-35 [PubMed] Related Publications
OBJECTIVE: Carney complex (CNC) is a rare autosomal dominant multiple neoplasia syndrome characterized by the presence of endocrine and non-endocrine tumors. More than 125 different germline mutations of the protein Kinase A type 1-α regulatory subunit (PRKAR1A) gene have been reported. We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures.
DESIGN: Clinical case report.
CASE REPORT: A 53-year-old male with a medical history of surgically removed recurrent cardiac myxomas was evaluated for repeated low-pressure vertebral fractures and severe osteoporosis. Physical examination revealed spotty skin pigmentation of the lower extremities and papules in the nuchal and thoracic region. The presence of hypercortisolism due to micronodular adrenal disease and the history of cardiac myxomas suggested the diagnosis of CNC; the patient underwent detailed imaging investigation and genetic testing.
METHODS: Standard imaging and clinical testing; DNA was sequenced by the Sanger method.
RESULTS: Sequence analysis from peripheral lymphocytes DNA revealed a novel heterozygous point mutation at codon 172 of exon 2 (c.172G>T) of the PRKAR1A gene, resulting in early termination of the PRKAR1A transcript [p.Glu58Ter (E58X)].
CONCLUSION: We report a novel point mutation of the PRKAR1A gene in a patient with CNC who presented with significant osteoporosis and fractures. Low bone mineral density along with recurrent myxomas should point to the diagnosis of CNC.

Aras Y, Erguven M, Aktas E, et al.
Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro.
Neurol Res. 2016; 38(9):766-74 [PubMed] Related Publications
OBJECTIVES: Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro.
METHODS: Monolayer and spheroid cultures of the T98G human GBM cell line were treated with an IM and LiCl combination for 72 h. The cell proliferation index, apoptotic index, cell cycle distribution, apoptotic and anti-apoptotic protein levels, and cAMP level as well as the cellular morphology and ultrastructure were evaluated.
RESULTS: All applications inhibited cell proliferation and induced apoptosis. The most substantial decreases in cell proliferation and the caspase-3, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor-alpha (PDGFR-α), multidrug resistance protein-1 (MRP-1), aquaporin-4 (AQP-4) and cAMP levels were induced by the LiCl treatment, which exhibited more pronounced effects compared with the combination treatment. LiCl was less effective in decreasing the MK and B cell lymphoma-2 (Bcl-2) levels compared with the combination treatment. The most substantial decrease in the p170 levels was identified following the combination treatment, whereas IM induced the second greatest decrease. LiCl alone had no effect on the p170 levels. IM induced the most substantial decrease in the phospho-glycogen synthase kinase 3-beta (p-GSK-3β)/glycogen synthase kinase 3-beta (GSK-3β) ratio, and LiCl induced the second most substantial decrease. Both LiCl and the combination treatment induced G2 + M arrest, whereas IM induced G0 + G1 arrest after 72 h of exposure. An apoptotic appearance and autophagic vacuoles were commonly identified in the LiCl, combination and IM groups, respectively.
CONCLUSIONS: The combination of IM and LiCl exhibited an antagonist effect, and MK had a role at this antagonism.

Khan MA, El-Gamal MI, Oh CH
A Progressive Review of V600E-B-RAF-Dependent Melanoma and Drugs Inhibiting It.
Mini Rev Med Chem. 2017; 17(4):351-365 [PubMed] Related Publications
B-RAF gene is a component of the MAPK pathway that plays a very important role in cell division, survival, proliferation, and many other cellular functions. Mutations of the B-RAF (such as V600E-B-RAF) lead to melanoma, which is one of the leading causes of death worldwide. R&D progress is being done aiming at improved therapy in the future. The existing melanoma therapy is left out with poor overall survival, drug resistance, and many side effects. With the recent approval of new drugs, there is a hope for melanoma patients for complete cure and better life quality. However, there is still a need for improved, safe, and complete therapy for advanced melanoma. This review describes melanoma caused by V600E-B-RAF gene mutation, its pathway, drugs available and recently approved drugs, and future prospects to be overcome.

Massobrio L, Nasti S, Martinuzzi C, et al.
Mutation Analysis of PRKAR1A Gene in a Patient with Atrial Myxoma.
Clin Lab. 2016; 62(4):731-4 [PubMed] Related Publications
BACKGROUND: Intracardiac myxomas are frequent benign tumors of the heart and typically localize in the left atri- um and interatrial septum. When myxomas generate at other sites, they are designated as atypical. Mutations in the PRKAR1A gene (a tumor suppressor gene that encodes a protein kinase A [PKA] regulatory 1-alpha subunit) have been identified in both syndromic and non-syndromic cardiac atypical myxomas.
METHODS: We report the case of a 33-year old woman suffering from night fever, weight loss, asthenia, and progressive dyspnea.
RESULTS: The blood laboratory tests revealed microcytic anemia, leukocytosis, thrombocytosis, increased serum levels of C-reactive protein level, and negative blood cultures. Physical examination also demonstrated a 2/6 systolic murmur. Transthoracic and trans-esophageal echocardiography showed a voluminous, mobile mass in the left atrium with a secondary dynamic obstruction of the left cardiac chamber and a significant functional mitral stenosis. A myxoma was supposed and the patient underwent surgery. Histologically, the lesion was identified as myxomatous tumor with gelatinous pattern. No germline mutations of the PRKAR1A gene were detected. The postoperative course did not present any complications, and the patient was discharged on the sixth postoperative day in good clinical condition. Accordingly, there was an improvement in the laboratory tests' results and a resolution of symptoms.
CONCLUSIONS: The patient presented an atrial giant gelatinous myxoma with peculiarity of fever of unknown origin, without PRKAR1A gene germline mutations.

Nanba K, Omata K, Tomlins SA, et al.
Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations.
Eur J Endocrinol. 2016; 175(2):K1-6 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
OBJECTIVE: Co-secretion of cortisol and aldosterone can be observed in adrenal adenomas. The aim of this study was to investigate the molecular characteristics of a co-existing aldosterone- and a cortisol-producing adenoma (CPA) in the same patient.
DESIGN AND METHODS: Two different adenomas within the same adrenal gland from a 49-year-old female patient with primary aldosteronism (PA) and Cushing's syndrome (CS) were studied. Multiple formalin-fixed paraffin-embedded tumor blocks were used for the analysis. Immunohistochemistry (IHC) was performed using a specific antibody against aldosterone synthase (CYP11B2). DNA and RNA were isolated separately from CYP11B2-positive and -negative tumor regions based on CYP11B2 IHC results.
RESULTS: CYP11B2 IHC clearly demonstrated that three pieces from one adenoma were positive for CYP11B2 and the remaining three from the other adenoma were negative for CYP11B2. In quantitative real-time RT-PCR, CYP11B2 mRNA was upregulated in CYP11B2-positive tumor specimens (219-fold vs CYP11B2-negative tumor specimens). Targeted next-generation sequencing (NGS) detected novel KCNJ5 gene mutations (p.T148I/T149S, present in the same reads) and a PRKACA gene hotspot mutation (p.L206R) in the CYP11B2-positive and -negative tumors, respectively. Sanger sequencing of DNA from each tumor specimen (CYP11B2-positive tumor, n=3; CYP11B2-negative tumor, n=3) showed concordant results with targeted NGS.
CONCLUSION: Our findings illustrate the co-existence of two different adrenocortical adenomas causing the concurrent diagnosis of PA and CS in the same patient. Molecular analysis was able to demonstrate that the two diseases resulted from independent somatic mutations seen in double adrenocortical adenomas.

Ha SH, Lee JM, Kwon KM, et al.
Exogenous and Endogeneous Disialosyl Ganglioside GD1b Induces Apoptosis of MCF-7 Human Breast Cancer Cells.
Int J Mol Sci. 2016; 17(5) [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Gangliosides have been known to play a role in the regulation of apoptosis in cancer cells. This study has employed disialyl-ganglioside GD1b to apoptosis in human breast cancer MCF-7 cells using exogenous treatment of the cells with GD1b and endogenous expression of GD1b in MCF-7 cells. First, apoptosis in MCF-7 cells was observed after treatment of GD1b. Treatment of MCF-7 cells with GD1b reduced cell growth rates in a dose and time dependent manner during GD1b treatment, as determined by XTT assay. Among the various gangliosides, GD1b specifically induced apoptosis of the MCF-7 cells. Flow cytometry and immunofluorescence assays showed that GD1b specifically induces apoptosis in the MCF-7 cells with Annexin V binding for apoptotic actions in early stage and propidium iodide (PI) staining the nucleus of the MCF-7 cells. Treatment of MCF-7 cells with GD1b activated apoptotic molecules such as processed forms of caspase-8, -7 and PARP (Poly(ADP-ribose) polymerase), without any change in the expression of mitochondria-mediated apoptosis molecules such as Bax and Bcl-2. Second, to investigate the effect of endogenously produced GD1b on the regulation of cell function, UDP-gal: β1,3-galactosyltransferase-2 (GD1b synthase, Gal-T2) gene has been transfected into the MCF-7 cells. Using the GD1b synthase-transfectants, apoptosis-related signal proteins linked to phenotype changes were examined. Similar to the exogenous GD1b treatment, the cell growth of the GD1b synthase gene-transfectants was significantly suppressed compared with the vector-transfectant cell lines and transfection activated the apoptotic molecules such as processed forms of caspase-8, -7 and PARP, but not the levels of expression of Bax and Bcl-2. GD1b-induced apoptosis was blocked by caspase inhibitor, Z-VAD. Therefore, taken together, it was concluded that GD1b could play an important role in the regulation of breast cancer apoptosis.

Zhang L, Li X, Dong W, et al.
Mmu-miR-1894-3p Inhibits Cell Proliferation and Migration of Breast Cancer Cells by Targeting Trim46.
Int J Mol Sci. 2016; 17(4) [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the lung metastasis of 4TO7 mouse breast cancer cells by 86.7% in mouse models. Mmu-miR-1894-3p was the functional mature form of miR-1894 and significantly decreased the lung metastasis of 4TO7 cells by 90.8% in mouse models. A dual-luciferase reporter assay indicated that mmu-miR-1894-3p directly targeted the tripartite motif containing 46 (Trim46) 3'-untranslated region (UTR) and downregulated the expression of Trim46 in 4TO7 cells. Consistent with the effect of mmu-miR-1894-3p, knockdown of Trim46 inhibited the experimental lung metastasis of 4TO7 cells. Moreover, knockdown of human Trim46 also prohibited the cell proliferation, migration and wound healing of MBA-MD-231 human breast cancer cells. These results suggested that the effect of knockdown of Trim46 alone was sufficient to recapitulate the effect of mmu-miR-1894 on the metastasis of the breast cancer cells in mouse and that Trim46 was involved in the proliferation and migration of mouse and human breast cancer cells.

Chuang WL, Lin PY, Lin HC, Chen YL
The Apoptotic Effect of Ursolic Acid on SK-Hep-1 Cells is Regulated by the PI3K/Akt, p38 and JNK MAPK Signaling Pathways.
Molecules. 2016; 21(4):460 [PubMed] Related Publications
Ursolic acid (UA) is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.

Zhang J, Zhang HY, Wang J, et al.
GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways.
Int J Mol Sci. 2016; 17(4):470 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Gastric cancer, which is the most common malignant gastrointestinal tumor, has jumped to the third leading cause of cancer-related mortality worldwide. It is of great importance to identify novel and potent drugs for gastric cancer treatment. P21-activated kinase 4 (PAK4) has emerged as an attractive target for the development of anticancer drugs in consideration of its vital functions in tumorigenesis and progression. In this paper, we reported that GL-1196, as a small molecular compound, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclinD1 pathway and CDK4/6 expression. Moreover, GL-1196 prominently inhibited the invasion of human gastric cancer cells in parallel with blockage of the PAK4/LIMK1/cofilin pathway. Interestingly, GL-1196 also inhibited the formation of filopodia and induced cell elongation in SGC7901 and BGC823 cells. Taken together, these results provided novel insights into the potential therapeutic strategy for gastric cancer.

Bourguignon LY
Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression.
Int J Mol Sci. 2016; 17(4):517 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20-25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients.

Liang Y, Liu Y, Hou B, et al.
CREB-regulated transcription coactivator 1 enhances CREB-dependent gene expression in spinal cord to maintain the bone cancer pain in mice.
Mol Pain. 2016; 12 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
BACKGROUND: cAMP response element binding protein (CREB)-dependent gene expression plays an important role in central sensitization. CREB-regulated transcription coactivator 1 (CRTC1) dramatically increases CREB-mediated transcriptional activity. Brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, and miRNA-212/132, which are highly CREB responsive, function downstream from CREB/CRTC1 to mediate activity-dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signaling. This study aimed to investigate the role of spinal CRTC1 in the maintenance of bone cancer pain using an RNA interference method.
RESULTS: Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeNCrlVr mice to induce bone cancer pain. Western blotting was applied to examine the expression of spinal phospho-Ser133 CREB and CRTC1. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CRTC1-small interfering RNA (siRNA) on nociceptive behaviors and on the upregulation of CREB/CRTC1-target genes associated with bone cancer pain. Inoculation of osteosarcoma cells induced progressive mechanical allodynia and spontaneous pain, and resulted in upregulation of spinal p-CREB and CRTC1. Repeated intrathecal administration with Adenoviruses expressing CRTC1-siRNA attenuated bone cancer-evoked pain behaviors, and reduced CREB/CRTC1-target genes expression in spinal cord, including BDNF, NR2B, and miR-212/132.
CONCLUSIONS: Upregulation of CRTC1 enhancing CREB-dependent gene transcription in spinal cord may play an important role in bone cancer pain. Inhibition of spinal CRTC1 expression reduced bone cancer pain. Interruption to the positive feedback circuit between CREB/CRTC1 and its targets may contribute to the analgesic effects. These findings may provide further insight into the mechanisms and treatment of bone cancer pain.

Wang YW, Chen X, Ma R, Gao P
Understanding the CREB1-miRNA feedback loop in human malignancies.
Tumour Biol. 2016; 37(7):8487-502 [PubMed] Related Publications
cAMP response element binding protein 1 (CREB1, CREB) is a key transcription factor that mediates transcriptional responses to a variety of growth factors and stress signals. CREB1 has been shown to play a critical role in development and progression of tumors. MicroRNAs (miRNAs) are a class of non-coding RNAs. They post-transcriptionally regulate gene expression through pairing with the 3'-UTR of their target mRNAs and thus regulate initiation and progression of various types of human cancers. Recent studies have demonstrated that a number of miRNAs can be transcriptionally regulated by CREB1. Interestingly, CREB1 expression can also be modulated by miRNAs, thus forming a feedback loop. This review outlines the functional roles of CREB1, miRNA, and their interactions in human malignancies. This will help to define a relationship between CREB1 and miRNA in human cancer and develop novel therapeutic strategies.

Park SA, Lee JW, Herbst RS, Koo JS
GSK-3α Is a Novel Target of CREB and CREB-GSK-3α Signaling Participates in Cell Viability in Lung Cancer.
PLoS One. 2016; 11(4):e0153075 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Overexpression or activation of cyclic AMP-response element-binding protein (CREB) has been known to be involved in several human malignancies, including lung cancer. Genes regulated by CREB have been reported to suppress apoptosis, induce cell proliferation, inflammation, and tumor metastasis. However, the critical target genes of CREB in lung cancer have not been well understood. Here, we identified GSK-3α as one of the CREB target genes which is critical for the viability of lung cancer cells. The CREB knockdown significantly reduced the expression of GSK-3α and the direct binding of CREB on the promoter of GSK3A was identified. Kaplan-Meier analysis with a public database showed a prognostic significance of aberrant GSK-3α expression in lung cancer. Inhibition of GSK-3α suppressed cell viability, colony formation, and tumor growth. For the first time, we demonstrated that GSK-3α is regulated by CREB in lung cancer and is required for the cell viability. These findings implicate CREB-GSK-3α axis as a novel therapeutic target for lung cancer treatment.

Wang J, Yang ZH, Chen H, et al.
Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer.
BMC Cancer. 2016; 16:257 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
BACKGROUND: Nurr1, a member of the orphan receptor family, plays an important role in several types of cancer. Our previous work demonstrated that increased expression of Nurr1 plays a significant role in the initiation and progression of prostate cancer (PCa), though the mechanisms for regulation of Nurr1 expression remain unknown. In this study, we investigated the hypothesis that Nemo-like kinase (NLK) is a key regulator of Nurr1 expression in PCa.
METHODS: Immunohistochemistry and Western blot analysis were used to evaluate levels of NLK and Nurr1 in prostatic tissues and cell lines. The effects of overexpression or knockdown of Nurr1 were evaluated in PCa cells through use of PCR, Western blots and promoter reporter assays. The role of Nurr1 promoter cis element was studied by creation of two mutant Nurr1 promoter luciferase constructs, one with a mutated NF-κB binding site and one with a mutated CREB binding site. In addition, three specific inhibitors were used to investigate the roles of these proteins in transcriptional activation of Nurr1, including BAY 11-7082 (NF-κB inhibitor), KG-501 (CREB inhibitor) and ICG-001 (CREB binding protein, CBP, inhibitor). The function of CBP in NLK-mediated regulation of Nurr1 expression was investigated using immunofluorescence, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation assays (ChIPs).
RESULTS: NLK expression was inversely correlated with Nurr1 expression in prostate cancer tissues and cell lines. Overexpression of NLK suppressed Nurr1 promoter activity, leading to downregulation of Nurr1 expression. In contrast, knockdown of NLK demonstrated opposite results, leading to upregulation of Nurr1. When compared with the wild-type Nurr1 promoter, mutation of NF-κB- and CREB-binding sites of the Nurr1 promoter region significantly reduced the upregulation of Nurr1 induced by knockdown of NLK in LNCaP cells; treatment with inhibitors of CREB, CBP and NF-κB led to similar results. We also found that NLK directly interacts with CBP, that knockdown of NLK significantly increases the recruitment of CBP to both NF-κB- and CREB-binding sites, and that regulation of NLK on Nurr1 expression is abrogated by knockdown of CBP.
CONCLUSIONS: Our results suggest that NLK inhibits transcriptional activation of Nurr1 gene by impeding CBP's role as a co-activator of NF-κB and CREB in prostate cancer.

Rong Y, Yuan CH, Qu Z, et al.
Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2.
Sci Rep. 2016; 6:23824 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Chemotherapies often induce drug-resistance in cancer cells and simultaneously stimulate proliferation and activation of Myeloid-Derived Suppressor Cells (MDSCs) to inhibit anti-tumor T cells, thus result in poor prognosis of patients with breast cancers. To date, the mechanism underlying the expansion of MDSCs in response to chemotherapies is poorly understood. In the present study, we used in vitro cell culture and in vivo animal studies to demonstrate that doxorubicin-resistant breast cancer cells secret significantly more prostaglandin E2 (PGE2) than their parental doxorubicin-sensitive cells. The secreted PGE2 can stimulate expansion and polymerization of MDSCs by directly target to its receptors, EP2/EP4, on the surface of MDSCs, which consequently triggers production of miR-10a through activating PKA signaling. More importantly, activated MDSCs can inhibit CD4(+)CD25(-) T cells as evidenced by reduced proliferation and IFN-γ release. In order to determine the molecular pathway that involves miR-10a mediated activation of MDSCs, biochemical and pharmacological studies were carried out. We found that miR-10a can activate AMPK signaling to promote expansion and activation of MDSCs. Thus, these results reveal, for the first time, a novel role of PGE2/miR-10a/AMPK signaling axis in chemotherapy-induced immune resistance, which might be targeted for treatment of chemotherapy resistant tumors.

Liu X, Xiao ZD, Han L, et al.
LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress.
Nat Cell Biol. 2016; 18(4):431-42 [PubMed] Article available free on PMC after 01/08/2017 Related Publications
Long non-coding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. However, the potential involvement of lncRNAs in kinase signalling remains largely unknown. AMP-activated protein kinase (AMPK) acts as a critical sensor of cellular energy status. Here we show that the lncRNA NBR2 (neighbour of BRCA1 gene 2) is induced by the LKB1-AMPK pathway under energy stress. On energy stress, NBR2 in turn interacts with AMPK and promotes AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation during energy stress. Depletion of NBR2 attenuates energy-stress-induced AMPK activation, resulting in unchecked cell cycling, altered apoptosis/autophagy response, and increased tumour development in vivo. NBR2 is downregulated and its low expression correlates with poor clinical outcomes in some human cancers. Together, the results of our study uncover a mechanism coupling lncRNAs with metabolic stress response, and provides a broad framework to understand further the regulation of kinase signalling by lncRNAs.

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