Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001511 (Adhesion)
 5,955 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evasion of immune surveillance is a key step in malignant progression. Interactions between transformed hematopoietic cells and their environment may initiate events that confer resistance to apoptosis and facilitate immune evasion. In this report, we demonstrate that beta(1) integrin-mediated adhesion to fibronectin inhibits CD95-induced caspase-8 activation and apoptosis in hematologic tumor cell lines. This adhesion-dependent inhibition of CD95-mediated apoptosis correlated with enhanced c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long (c-FLIP(L)) cytosolic solubility compared with nonadhered cells. Cytosolic c-FLIP(L) protein preferentially associated with cytosolic Fas-associated death domain protein (FADD) and localized to the death-inducing signal complex after CD95 ligation in adherent cells. The incorporation of c-FLIP(L) in the death-inducing signal complex prevented procaspase-8 processing and activation of the effector phase of apoptosis. Adhesion to fibronectin increased c-FLIP(L) cytosolic solubility and availability for FADD binding by redistributing c-FLIP(L) from a preexisting membrane-associated fraction. Increased cytosolic availability of c-FLIP(L) for FADD binding was not related to increased levels of RNA or protein synthesis. These data show that adhesion of anchorage-independent cells to fibronectin provides a novel mechanism of resistance to CD95-mediated programmed cell death by regulating the cellular localization and availability of c-FLIP(L).
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PMID:Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. 1185 50

Adhesion of many cell types to the extracellular matrix is essential to maintain their survival. In the absence of integrin-mediated signals, normal epithelial cells undergo a form of apoptosis termed anoikis. It has been proposed that the activation of initiator caspases is an early event in anoikis, resulting in Bid cleavage and cytochrome c release from mitochondria. We have previously demonstrated that the loss of integrin signaling in mammary epithelial cells results in apoptosis and that this is dependent upon translocation of Bax from the cytosol to the mitochondria. In this paper, we ask whether caspases are required for Bax activation and the associated changes within mitochondria. We show that Bax activation occurs extremely rapidly, within 15 min after loss of integrin-mediated adhesion to extracellular matrix. The conformational changes associated with Bax activation are independent of caspases including the initiator caspase-8. We also examined downstream events in the apoptosis program and found that cytochrome c release occurs after a delay of at least 1 h, with subsequent activation of the effector caspase-3. This delay is not due to a requirement for new protein synthesis, since cycloheximide has no effect on the kinetics of Bax activation, cytochrome c release, caspase-3 cleavage, or apoptosis. Together, our data indicate that the cellular decision for anoikis in mammary epithelial cells occurs in the absence of caspase activation. Moreover, although the conformational changes in Bax are rapid and synchronous, the subsequent events occur stochastically and with considerable delays.
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PMID:Early events in the anoikis program occur in the absence of caspase activation. 1262 Oct 32

Osteoporosis caused by estrogen deficiency is characterized by enhanced bone resorption mediated by osteoclasts. Adhesion to bone matrix and survival of differentiated osteoclasts is necessary to resorb bone. The aim of our study was to investigate the in vitro effects of estradiol on murine osteoclasts. RAW 264.7 cells treated with 30 ng/ml RANK-L were used as a model for osteoclastogenesis. Estradiol (10(-8)M) for 5 days induced an inhibition of osteoclast differentiation and beta3 expression. Estradiol inhibited significantly the adhesion of mature osteoclasts by 30%. Furthermore estradiol-induced apoptosis shown by with nuclear condensation and Bax/Bcl2 ratio. In addition, estradiol enhanced caspase-3, -8 and -9 activities. This effect completely disappeared using specific caspase-8 inhibitor. However, increased caspase-3 activity by estradiol was observed in the presence of caspase-9 inhibitor, indicating the preferential involvement of caspase-8 pathway. Fas and FasL mRNA expression was not regulated by estradiol. However, estradiol enhanced caspase-3 activity in Fas-induced apoptosis on mature osteoclasts, suggesting that this might interact with the Fas-signaling pathway. These data suggest that estradiol decreases bone resorption by several mechanisms including adhesion and apoptosis of osteoclasts.
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PMID:Estradiol inhibits adhesion and promotes apoptosis in murine osteoclasts in vitro. 1662 21

Integrin-mediated adhesion of leukemia cells to extracellular matrix proteins reduces apoptosis following radiation-induced genotoxic injury. To evaluate the role of integrin-linked kinase (ILK) in this process, HL60 human acute promyelocytic leukemia cells were stably transfected with ILK wild-type or kinase-hyperactive overexpression vectors. Suspension or fibronectin (FN) adhesion cultures were irradiated with X-rays and processed for measurement of apoptosis, mitochondrial transmembrane potential and caspase activation. Adhesion to FN pronouncedly reduced radiation-induced apoptosis of HL60 cells and vector controls. Intriguingly, overexpressed ILK enhanced apoptosis after irradiation by combined activation of caspase-3 through caspase-8 and -9 in irradiated FN cultures. Irradiation of ILK suspension cultures lacked caspase-8 activation, but showed serial cleavage of caspase-9, -3 and poly (ADP-ribose) polymerase. These findings further characterize the cell death-promoting function of ILK in DNA-damaged cells. Moreover, ILK might represent a potential therapeutic target for innovative chemo- and radiooncological approaches in hematological malignancies.
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PMID:Integrin-linked kinase interacts with caspase-9 and -8 in an adhesion-dependent manner for promoting radiation-induced apoptosis in human leukemia cells. 1693 72

Focal Adhesion Kinase (FAK) is overexpressed in many types of tumors and plays an important role in survival. We developed a novel approach, targeting FAK-protein interactions by computer modeling and screening of NCI small molecule drug database. In this report we targeted FAK and Mdm-2 protein interaction to decrease tumor growth. By macromolecular modeling we found a model of FAK and Mdm-2 interaction and performed screening of > 200,000 small molecule compounds from NCI database with drug-like characteristics, targeting the FAK-Mdm-2 interaction. We identified 5';-O-Tritylthymidine, called M13 compound that significantly decreased viability in different cancer cells. M13 was docked into the pocket of FAK and Mdm-2 interaction and was directly bound to the FAK-N terminal domain by ForteBio Octet assay. In addition, M13 compound affected FAK and Mdm-2 levels and decreased complex of FAK and Mdm-2 proteins in breast and colon cancer cells. M13 re-activated p53 activity inhibited by FAK with Mdm-2 promoter. M13 decreased viability, clonogenicity, increased detachment and apoptosis in a dose-dependent manner in BT474 breast and in HCT116 colon cancer cells in vitro. M13 decreased FAK, activated p53 and caspase-8 in both cell lines. In addition, M13 decreased breast and colon tumor growth in vivo. M13 activated p53 and decreased FAK in tumor samples consistent with decreased tumor growth. The data demonstrate a novel approach for targeting FAK and Mdm-2 protein interaction, provide a model of FAK and Mdm-2 interaction, identify M13 compound targeting this interaction and decreasing tumor growth that is critical for future targeted therapeutics.
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PMID:A small-molecule inhibitor, 5'-O-tritylthymidine, targets FAK and Mdm-2 interaction, and blocks breast and colon tumorigenesis in vivo. 2229 71