scholarly journals Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer

2021 ◽  
Author(s):  
Rehman Ata ◽  
Costin N. Antonescu
Keyword(s):  
Cell Survival ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Metabolic Flux ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
And Migration ◽  
The Impact

Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular signaling pathways and in facilitating metastasis. Integrins and associated proteins are regulated by control of transcription, membrane traffic, and degradation, as well as by a number of post-translational modifications including glycosylation, allowing integrin function to be modulated to conform to various cellular needs and environmental conditions. In this review, we examine the control of integrin function by cell metabolism, and the impact of this regulation in cancer. Within this context, nutrient sufficiency or deprivation is sensed by a number of metabolic signaling pathways such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) 1, which collectively control integrin function by a number of mechanisms. Moreover, metabolic flux through specific pathways also controls integrins, such as by control of integrin glycosylation, thus impacting integrin-dependent cell adhesion and migration. Integrins also control various metabolic signals and pathways, establishing the reciprocity of this regulation. As cancer cells exhibit substantial changes in metabolism, such as a shift to aerobic glycolysis, enhanced glucose utilization and a heightened dependence on specific amino acids, the reciprocal regulation of integrins and metabolism may provide important clues for more effective treatment of various cancers.

scholarly journals Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer

2021 ◽  
Author(s):  
Rehman Ata ◽  
Costin N. Antonescu
Keyword(s):  
Cell Survival ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Metabolic Flux ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
And Migration ◽  
The Impact

Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular signaling pathways and in facilitating metastasis. Integrins and associated proteins are regulated by control of transcription, membrane traffic, and degradation, as well as by a number of post-translational modifications including glycosylation, allowing integrin function to be modulated to conform to various cellular needs and environmental conditions. In this review, we examine the control of integrin function by cell metabolism, and the impact of this regulation in cancer. Within this context, nutrient sufficiency or deprivation is sensed by a number of metabolic signaling pathways such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) 1, which collectively control integrin function by a number of mechanisms. Moreover, metabolic flux through specific pathways also controls integrins, such as by control of integrin glycosylation, thus impacting integrin-dependent cell adhesion and migration. Integrins also control various metabolic signals and pathways, establishing the reciprocity of this regulation. As cancer cells exhibit substantial changes in metabolism, such as a shift to aerobic glycolysis, enhanced glucose utilization and a heightened dependence on specific amino acids, the reciprocal regulation of integrins and metabolism may provide important clues for more effective treatment of various cancers.

scholarly journals PAK1 and PAK2 in the cell metabolism regulation

2021 ◽  
Author(s):  
Tereza Koranova ◽  
Lukas Dvoracek ◽  
Dana Grebenova ◽  
Pavla Roselova ◽  
Adam Obr ◽  
...  
Keyword(s):  
Cell Lines ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Cell Interaction ◽  
Metabolic Phenotype ◽  
Knock Out ◽  
Metabolism Regulation ◽  
Group I ◽  
And Migration ◽  
The Impact

P21-activated kinases (PAK) regulate processes associated with cytoskeletal rearrangements, such as cell division, adhesion, and migration. Possible regulatory role of PAK in the cell metabolism is little explored, but increasing evidence suggests that a cell metabolic phenotype is related to cell interaction with the microenvironment. We analyzed the impact of PAK inhibition by small molecule inhibitors, small interfering RNA, or by gene knock-out on the rates of mitochondrial respiration and aerobic glycolysis. Pharmacological inhibition of PAK group I by IPA-3 induced a strong decrease of the both metabolic rates in adherent cancer cell lines, leukemia/lymphoma cell lines, and primary leukemia cells. The effect of FRAX597, which inhibits PAK kinase activity only, was moderate, indicating that PAK non-kinase functions are essential for the cell metabolism. Selective downregulation or deletion of PAK2 was associated with a shift towards oxidative phosphorylation. However, the overall metabolic capacity was not substantially reduced by PAK1 or PAK2 deletion, possibly due to partial redundancy in PAK1/PAK2 regulatory roles.

scholarly journals Caffeine Inhibits EGF-Stimulated Trophoblast Cell Motility through the Inhibition of mTORC2 and Akt

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4502-4510 ◽  
Author(s):  
Isobelle Grant ◽  
Judith E. Cartwright ◽  
Brooke Lumicisi ◽  
Alison E. Wallace ◽  
Guy S. Whitley
Keyword(s):  
Cell Motility ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Pregnancy Loss ◽  
Mammalian Target Of Rapamycin ◽  
First Trimester ◽  
Trophoblast Invasion ◽  
Intracellular Signaling Pathways

Impaired trophoblast invasion is associated with pregnancy disorders such as early pregnancy loss and preeclampsia. There is evidence to suggest that the consumption of caffeine during pregnancy may increase the risk of pregnancy loss; however, little is known about the direct effect of caffeine on normal trophoblast biology. Our objectives were to examine the effect of caffeine on trophoblast migration and motility after stimulation with epidermal growth factor (EGF) and to investigate the intracellular signaling pathways involved in this process. Primary first-trimester extravillous trophoblasts (EVT) and the EVT-derived cell line SGHPL-4 were used to study the effect of caffeine on EGF-stimulated cellular motility using time-lapse microscopy. SGHPL-4 cells were further used to study the effect of caffeine and cAMP on EGF-stimulated invasion of fibrin gels. The influence of caffeine and cAMP on EGF-stimulated intracellular signaling pathways leading to the activation of Akt were investigated by Western blot analysis. Caffeine inhibits both EGF-stimulated primary EVT and SGHPL-4 cell motility. EGF stimulation activates phosphatidylinositol 3-kinase, and Akt and caffeine inhibit this activation. Although cAMP inhibits both motility and invasion, it does not inhibit the activation of Akt, indicating that the effects of caffeine seen in this study are independent of cAMP. Further investigation indicated a role for mammalian target of rapamycin complex 2 (mTORC2) as a target for the inhibitory effect of caffeine. In conclusion, we demonstrate that caffeine inhibits EGF-stimulated trophoblast invasion and motility in vitro and so could adversely influence trophoblast biology in vivo.

Cucurbitacins: A Systematic Review of the Phytochemistry and Anticancer Activity

2015 ◽  
Vol 43 (07) ◽  
pp. 1331-1350 ◽  
Author(s):  
Yuee Cai ◽  
Xiefan Fang ◽  
Chengwei He ◽  
Peng Li ◽  
Fei Xiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mapk Signaling ◽  
Research Progress ◽  
Migration And Invasion ◽  
Invasion And Migration ◽  
Cycle Arrest ◽  
Anticancer Effects ◽  
And Migration

Cucurbitacins are highly oxidized tetracyclic triterpenoids that are widely present in traditional Chinese medicines (Cucurbitaceae family), possess strong anticancer activity, and are divided into 12 classes from A to T with over 200 derivatives. The eight most active cucurbitacin components against cancer are cucurbitacin B, D, E, I, IIa, L glucoside, Q, and R. Their mechanisms of action include antiproliferation, inhibition of migration and invasion, proapoptosis, and cell cycle arrest promotion. Cucurbitacins are also found to be the inhibitors of JAK-STAT3, Wnt, PI3K/Akt, and MAPK signaling pathways, which play important roles in the apoptosis and survival of cancer cells. Recently, new studies have discovered synergistic anticancer effects by using cucurbitacins together with clinically approved chemotherapeutic drugs, such as docetaxel and methotrexate. This paper provides a summary of recent research progress on the anticancer property of cucurbitacins and the various intracellular signaling pathways involved in the regulation of cancer cell proliferation, death, invasion, and migration. Therefore, cucurbitacins are a class of promising anticancer drugs to be used alone or be intergraded in current chemotherapies and radiotherapies to treat many types of cancers.

scholarly journals P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization

2021 ◽  
Author(s):  
Pinaki Chaudhuri ◽  
Andrew H. Smith ◽  
Priya Putta ◽  
Linda M. Graham ◽  
Michael A. Rosenbaum
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Oxidation Products ◽  
In Vivo Studies ◽  
Subsequent Increase ◽  
Lipid Oxidation Products ◽  
The Impact

Lipid oxidation products, including lysophosphatidylcholine (lysoPC) inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo, in part by activating phosphatidylinositol 3-kinase (PI3K), which increases the externalization of canonical transient receptor potential 6 (TRPC6) channels and the subsequent increase in intracellular calcium. Inhibition of PI3K is a potential method to decrease TRPC6 activation and restore migration, but PI3K is involved in multiple intracellular signaling pathways and has multiple downstream effectors. The goal of this study is to identify the specific p110 catalytic subunit isoforms responsible for lysoPC-induced TRPC6 externalization to identify a target for intervention while minimizing impact on alternative signaling pathways. Down-regulation of the p110α and p110δ isoforms, but not the p110β or p110γ isoforms, with small interfering RNA significantly decreased phosphatidylinositol (3,4,5)-trisphosphate production and TRPC6 externalization, and significantly improved EC migration in the presence of lysoPC. These results identify an additional role of p110α in EC and reveal for the first time a specific role of p110δ in EC, providing a foundation for subsequent in vivo studies to investigate the impact of p110 isoform inhibition on arterial healing after injury.

scholarly journals CSIG-05. S6K FEEDBACK REGULATION OF THE RECEPTOR TYROSINE KINASE AXL IN PTEN-DEFICIENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii28-ii28
Author(s):  
Pranjal Sarma ◽  
Kelli N Ennis ◽  
Collin Wetzel ◽  
David R Plas
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Metabolic Flux ◽  
Cell Metabolism ◽  
Single Agent ◽  
Feedback Regulation ◽  
Apoptosis Resistance ◽  
Nucleotide Synthesis ◽  
The Impact

Abstract Glioblastoma multiforme (GBM), the most aggressive type of malignant brain cancer in adults, harbors frequent mutations and/or deletions in the tumor suppressor gene PTEN leading to therapeutic resistance. In PTEN-deficient GBM, mTOR complex 1 (mTORC1) and the S6 kinases (S6Ks) mediate increased metabolism and apoptosis resistance. Previously we established that combining the LY-2584702 inhibitor of S6K1 with the BMS-777607 inhibitor of the AXL receptor tyrosine kinase (RTK) was selectively cytotoxic for PTEN-deficient GBM. Here we determined the impact of these inhibitors on S6K1 and S6K2 signal transduction and tumor cell metabolism. While combination of LY-2584702 with BMS-777607 was sufficient to prevent S6K phosphorylation of ribosomal protein S6 (rpS6), treatment with either drug as a single agent was not sufficient to suppress rpS6 phosphorylation. Genetic inactivation of S6Ks revealed that inactivation of S6K2 cooperated with LY-2584702 to prevent S6K substrate phosphorylation. Similarly, persistent S6K signaling in BMS777607-treated GBM cells was significantly reduced when S6K2 was targeted. These results indicate that S6K2 integrates signal transduction inputs from both PTEN-regulated and AXL-regulated pathways. Metabolomic analysis revealed combination effects of S6K and AXL inhibitors in reducing nucleotide precursor metabolic flux. We therefore propose that combination inhibition of S6K and AXL signaling compromises S6K-dependent nucleotide synthesis in PTEN-deficient GBM.

Prolyl hydroxylases as regulators of cell metabolism

2009 ◽  
Vol 37 (1) ◽  
pp. 291-294 ◽  
Author(s):  
Houda Boulahbel ◽  
Raúl V. Durán ◽  
Eyal Gottlieb
Keyword(s):  
Amino Acid ◽  
Cellular Response ◽  
Oxygen Sensing ◽  
Cell Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Oxygen Depletion ◽  
Animal Cells ◽  
Prolyl Hydroxylases ◽  
Amino Acid Availability

Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.

TRAF6 and C-myb Show Novel Functions in the Nucleus of Lymphoma B Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2376-2376 ◽  
Author(s):  
Lan V. Pham ◽  
Yen-Chiu Lin-Lee ◽  
Hai-Jun Zhou ◽  
Archito T. Tamayo ◽  
Linda C. Yoshimura ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Growth ◽  
B Cell ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Tnf Receptor ◽  
Growth And Survival ◽  
Survival Pathways ◽  
Interfering Rna

Abstract The tumor necrosis factor (TNF) family (TNF-R; CD40; BAFF-R) plays a key role in neoplastic as well as normal B cell growth and survival mechanisms. TNF receptor-associated factor-6 (TRAF-6) is an adapter molecule that regulates several important signaling pathways critical for cell growth and cell survival. It is a member of seven closely related TRAF proteins that serve as signaling molecules, coupling to TNF-receptor superfamily to intracellular signaling, particularly in the CD40 Signalosome. TRAF6 has shown to be over-expressed and play an important role in cell growth and cell survival through the activation of the key transcription factor NF-kB in aggressive non-Hodgkin’s lymphoma B cells (NHL-B), common B cell neoplasm that have been increasing in recent years. Although much of TRAF-6 functions have focused primarily as an adaptor molecule in signaling pathways in the cytoplasm, the role of TRAF-6 in other cellular compartments has not been investigated. Here, we demonstrate, by confocal microscopy as well as cellular fractionation studies that TRAF-6 resides not only in the cytoplasm but also in the nucleus of lymphoma B cells. Immunoprecipitation studies show that TRAF6 is auto-ubiquitinated in the cytoplasm but not in the nucleus, suggesting that nuclear TRAF6 functions differently than cytoplasmic TRAF6. Chromatin immunoprecipitation (ChiP) cloning assays using anti-TRAF6 polyclonal antibody reveal over 200 clones, one of which contains a 130 bp fragment belonging to the proximal 5′ end of the c-myb oncogene promoter. Further experiments demonstrate that nuclear TRAF6 co-localized with SUMO1 and c-myb, suggesting that TRAF-6 may enter the nucleus through SUMO1 interaction and serve as an E3 sumo ligase, in addition to its known adapter role in cytoplasmic signaling. Over-expression studies show that TRAF6 enhances c-myb sumoylation in lymphoma B cells, where this oncogene is over-expressed. C-myb correlates with TRAF6 protein and mRNA expressions in NHL-B cells, suggesting that TRAF6 may be involved in the modulation of c-myb expression through sumoylation, regulating key genes that are regulated by c-myb. Small interfering RNA (siRNA) targeting c-myb results in inhibition of lymphoma cell survival, suggesting that SUMO1/TRAF6/c-myb interactions are important in cell survival pathways in aggressive NHL-B. Such pathways could represent novel targets for the development of therapeutic agents for aggressive B cell lymphomas.

scholarly journals Proinsulin C-Peptide Enhances Cell Survival and Protects against Simvastatin-Induced Myotoxicity in L6 Rat Myoblasts

2019 ◽  
Vol 20 (7) ◽  
pp. 1654
Author(s):  
Sumia Essid ◽  
Alan Bevington ◽  
Nigel Brunskill
Keyword(s):  
Skeletal Muscle ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Akt Signaling ◽  
Skeletal Muscle Function ◽  
Repair Capacity ◽  
C Peptide ◽  
Myoblast Cell ◽  
Induced Apoptosis

The repair capacity of progenitor skeletal muscle satellite cells (SC) in Type 1 diabetes mellitus (T1DM) is decreased. This is associated with the loss of skeletal muscle function. In T1DM, the deficiency of C-peptide along with insulin is associated with an impairment of skeletal muscle functions such as growth, and repair, and is thought to be an important contributor to increased morbidity and mortality. Recently, cholesterol-lowering drugs (statins) have also been reported to increase the risk of skeletal muscle dysfunction. We hypothesised that C-peptide activates key signaling pathways in myoblasts, thus promoting cell survival and protecting against simvastatin-induced myotoxicity. This was tested by investigating the effects of C-peptide on the L6 rat myoblast cell line under serum-starved conditions. Results: C-peptide at concentrations as low as 0.03 nM exerted stimulatory effects on intracellular signaling pathways—MAP kinase (ERK1/2) and Akt. When apoptosis was induced by simvastatin, 3 nM C-peptide potently suppressed the apoptotic effect through a pertussis toxin-sensitive pathway. Simvastatin strongly impaired Akt signaling and stimulated the reactive oxygen species (ROS) production; suggesting that Akt signaling and oxidative stress are important factors in statin-induced apoptosis in L6 myoblasts. The findings indicate that C-peptide exerts an important protective effect against death signaling in myoblasts. Therefore, in T1DM, the deficiency of C-peptide may contribute to myopathy by rendering myoblast-like progenitor cells (involved in muscle regeneration) more susceptible to the toxic effects of insults such as simvastatin.

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