RGD-containing Peptides Activate S6K1 through β3 Integrin in Adult Cardiac Muscle Cells

Balasubramanian, Sundaravadivel; Kuppuswamy, Dhandapani

doi:10.1074/jbc.m303428200

Cited by 52 publications

(44 citation statements)

References 63 publications

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“…RAD001 triggered b3 up-regulation may then reflect an undesired feedback loop which counteracts the adhesion diminishing properties of this compound. In fact, studies on cardiomyocyte cultures have indicated that stimulation of b3 integrins reactivates mTOR related pathways [29], the process of which has been correlated to reduced drug efficacy [30]. This is corroborated by our own findings revealing a superior anti-tumor effect of VPA in both the tumor-endothelial coculture assay and the tumor matrix system, compared to RAD001.…”

Section: Discussionsupporting

confidence: 52%

Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells

Wedel

Hudak

Seibel

et al. 2011

Clin Exp Metastasis

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The concept of molecular tumor targeting might provide new hope in the treatment of advanced prostate cancer. We evaluated metastasis blocking properties of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and the mammalian target of rapamycin (mTOR) inhibitor RAD001 on prostate cancer cell lines. RAD001 or VPA were applied to PC-3 or LNCaP cells, either separately or in combination. Adhesion to vascular endothelium or to immobilized collagen, fibronectin or laminin was quantified. Migration and invasion were explored by a modified Boyden chamber assay. Integrin α and β subtypes were analyzed by flow cytometry, western blotting and RT-PCR. Effects of drug treatment on integrin related signaling, Akt and p70S6kinase activation, histone H3 and H4 acetylation were also determined. Separate application of RAD001 or VPA distinctly reduced tumor cell adhesion, migration and invasion, accompanied by elevated Akt activation and p70S6kinase de-activation. Integrin subtype expression was altered significantly by both compounds (VPA > RAD001). When both drugs were used in concert additive effects were observed on the migratory and invasive behavior but not on tumor-endothelium and tumor-matrix interaction. Separate mTOR or HDAC inhibition slows processes related to tumor metastasis. The RAD001-VPA combination showed advantage over VPA monotreatment with particular respect to migration and invasion. Ongoing studies are required to assess the relevance of VPA monotherapy versus VPA-RAD001 combination on tumor cell motility.

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Section: Discussionsupporting

confidence: 52%

Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells

Wedel

Hudak

Seibel

et al. 2011

Clin Exp Metastasis

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“…In fact, stimulation of h3 integrin with Arg-Gly-Asp peptide in isolated adult cardiomyocytes triggers activation of c-SRC accompanied by binding to p130CAS and phosphorylation of FAK Tyr925 [34]. In addition, activation of p70S6 kinase, via mTOR, MEK/ERK, and phosphatidylinositol 3-kinase is also promoted by Arg -Gly-Asp stimulation of h3 integrin in cardiomyocytes [35]. While these studies clearly indicate an important role of h3 integrin in isolated cardiomyocytes, its involvement in cardiac hypertrophy in vivo remains to be clarified.…”

Section: Integrin-linked Molecular Machinery Triggering Signal Transdmentioning

confidence: 93%

Integrin signalling: The tug-of-war in heart hypertrophy

Brancaccio

Hirsch

Notte

et al. 2006

Cardiovascular Research

162

132

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The mechanical stress imposed by hemodynamic overload on heart walls is a primary event in triggering the cardiac hypertrophic response. Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. In fact, integrins, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy program. In this review, we will discuss the role of the muscle-specific integrin isoform beta1D and of associated proteins such as FAK, melusin, vinculin, zyxin, VASP, and migfilin that are the most upstream elements ("initiators") activated by mechanical strain. These molecules trigger a coordinated downstream signaling cascade involving proteins such as AKT, RAS, and MAPKs that execute the biochemical program leading to cardiomyocyte hypertrophy. Better understanding of the functional role of the initiator elements is of key importance to developing novel strategies to control cardiac hypertrophy and prevent heart failure.

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“…The increase in translational capacity is supported by our observation of FN-induced expression of ribosomal protein genes, resulting in the highest z-score of the pathways examined (Table 3). It is known that hypertrophy and integrin activation increases the translational efficiency of ribosomal protein mRNAs (3,54). Therefore, it is likely that the abundance of ribosomal proteins increases during hypertrophy due to increased transcription and increased translation.…”

Section: Discussionmentioning

confidence: 99%

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

Chen

Huang

Stewart

et al. 2004

Physiological Genomics

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(FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype. extracellular matrix; integrin; ventricular remodeling; signal transduction; gene expression profiling OUTSIDE-IN SIGNALING CHARACTERIZES the cellular effects mediated by interaction of cellular receptors with the extracellular matrix. In neonatal rat ventricular myocytes (NRVM), clustering of integrin receptors induced by fibronectin (FN) (39,40) or RGD peptides (3) elicits a hypertrophic response, characterized by a 1.5-to 3-fold increase in cellular area and corresponding increases in global mRNA and protein synthesis, together with enhanced myofibrillogenesis and sarcomeric assembly. FN also induces increased formation of focal adhesions and costameres, which are sites of contact of extracellular matrix with integrins and associated cytoskeletal proteins associated with the Z-disks of the sarcomere (39). As in other models of hypertrophy, the hypertrophic response is accompanied by changes in gene expression, with increased expression of the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and fetal isoforms of sarcomeric proteins such as ␤-myosin heavy chain (␤MHC) and ␣-skeletal actin (␣SkA).The pathophysiological relevance of the FN-induced, integrin-mediated pathway is highlighted by the observation of increased deposition of FN in the extracellular matrix in animal models of cardiac hypertrophy and in patients with cardiac failure (5,20,22,29,42,45). The increased synthesis of FN is in part mediated...

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RGD-containing Peptides Activate S6K1 through β3 Integrin in Adult Cardiac Muscle Cells

Cited by 52 publications

References 63 publications

Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells

Impact of combined HDAC and mTOR inhibition on adhesion, migration and invasion of prostate cancer cells

Integrin signalling: The tug-of-war in heart hypertrophy

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

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