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PubMed2006

N-glycosylation of the beta-propeller domain of the integrin alpha5 subunit is essential for alpha5beta1 heterodimerization, expression on the cell surface, and its biological function.

The N-glycosylation of integrin alpha5beta1 is thought to play crucial roles in cell spreading, cell migration, ligand binding, and dimer formation, but the underlying mechanism remains unclear. To investigate the importance of the N-glycans of this integrin in detail, sequential site-directed mutagenesis was carried out to remove single or combined putative N-glycosylation sites on the alpha5 integrin. Removal of the putative N-glycosylation sites on the beta-propeller, Thigh, Calf-1, or Calf-2 domains of the alpha5 subunit resulted in a decrease in molecular weight compared with the wild type, suggesting that all of these domains contain attached N-glycans. Importantly, the absence of N-glycosylation sites (sites 1-5) on the beta-propeller resulted in the persistent association of integrin subunit with calnexin in the endoplasmic reticulum, which subsequently blocked heterodimerization and its expression on the cell surface. Interestingly, the activities for cell spreading and migration for the alpha5 subunit carrying only three potential N-glycosylation sites (3-5 sites) on the beta-propeller were comparable with those of the wild type. In contrast, mutation of these three sites resulted in a significant decrease in cell spreading as well as functional expression, although the total expression level of the Delta3-5 mutant on the cell surface was comparable with that of wild type. Furthermore, we found that site 5 is a most important site for its expression on the cell surface, whereas the S5 mutant did not show any biological functions. Taken together, this study reveals for the first time that the N-glycosylation on the beta-propeller domain of the alpha5 subunit is essential for heterodimerization and biological functions of alpha5beta1 integrin and might also be useful for studies of the molecular structure.

Animals↗
PubMed1999

Up-regulation of integrin alpha5 by a C-terminus four-amino-acid sequence of substance P (phenylalanine-glycine-leucine-methionine- amide) synergistically with insulin-like growth factor-1 in SV-40 transformed human corneal epithelial cells.

We previously reported that substance P and insulin-like growth factor-1 (IGF-1) synergistically facilitate corneal epithelial migration in vivo and in vitro. We investigated whether the substance P-derived tetrapeptide (phenylalanine-glycine-leucine-methionine-amide, FGLM) can up-regulate the receptors for fibronectin and cellular adhesion to fibronectin matrix in the presence or absence of IGF-1 in cultured SV-40 transformed human corneal epithelial (HCE) cells. The combination of both FGLM and IGF-1 and substance P and IGF-1 significantly increased the number of cells adhered to the fibronectin matrix and the expression of integrin alpha5. The synergistic effect of FGLM and IGF-1 on the adhesion of HCE cells to the fibronectin matrix is partly carried through up-regulation of integrin alpha5 expression in HCE cells. These results showed that the four-amino-acid sequence at the C-terminus of substance P completely mimics the substance P molecule in terms of synergism with IGF-1 on adhesion of epithelial cells to the fibronectin matrix.

Antigens, CD↗
PubMed1998

Macrophage-colony stimulating factor (M-CSF) regulates the expression of fibronectin and its alpha5 integrin receptor in human trophoblasts.

Macrophage-colony stimulating factor (M-CSF, CSF-1) is secreted by human trophoblasts as well as endometrial cells, while its receptor c-fms is abundantly expressed by the extravillous trophoblasts anchoring the placenta to the uterus, suggesting a role for M-CSF at the maternal-fetal interface. We investigated the effect of M-CSF on the expression of fibronectin and its receptor, the alpha5 integrin, in human trophoblasts. Exposure of trophoblasts to M-CSF produced a two to three-fold increase in fibronectin and alpha5 mRNA abundance at both 24 and 72 hours of culture. A dose-dependent increase in cellular fibronectin secretion into the culture medium was detected at both time points. Immunocytochemistry showed co-localization of cellular fibronectin and alpha5 in the cells, suggesting that attachment of trophoblasts to fibronectin is mediated in part by the alpha5beta1 integrin. We conclude that M-CSF increases fibronectin expression and secretion by the human trophoblasts, and up-regulates its specific receptor, the alpha5 integrin. We hypothesize that M-CSF may partake in the autocrine/paracrine mechanisms regulating trophoblast invasion during implantation.

Antigens, CD↗
PubMed1998

Identification of amino acid residues that form part of the ligand-binding pocket of integrin alpha5 beta1.

Arg-Arg-Glu-Thr-Ala-Trp-Ala (RRETAWA) is a novel ligand peptide for integrin alpha5 beta1, which blocks alpha5 beta1-mediated cell adhesion to fibronectin (Koivunen, E., Wang, B., and Ruoslahti, E. (1994) J. Cell Biol. 124, 373-380). Here we have localized the binding site for RRETAWA on alpha5 beta1 using inhibitory monoclonal antibodies (mAbs) and site-directed mutagenesis. A cyclic peptide containing this sequence (*CRRETAWAC*) had little effect on the binding of most anti-alpha5 and anti-beta1 mAbs to alpha5 beta1 but completely blocked binding of the anti-alpha5 mAb 16 in a directly competitive manner. Hence, the binding site of RRETAWA appears to closely overlap with the epitope of mAb 16. *CRRETAWAC* also acted as a direct competitive inhibitor of the binding of Arg-Gly-Asp (RGD)-containing fibronectin fragments to alpha5 beta1, suggesting that the binding site for RRETAWA is also closely overlapping with that for RGD. However, differences between the binding sites of RRETAWA and RGD were apparent in that (i) RGD peptides allosterically inhibited the binding of mAb 16 to alpha5 beta1, and (ii) several mAbs that perturbed binding of alpha5 beta1 to RGD had little effect on binding of alpha5 beta1 to RRETAWA. A double mutation in alpha5 (S156G/W157S) blocked the interaction of both RRETAWA and mAb 16 with alpha5 beta1 but had no effect on fibronectin binding or on the binding of other anti-alpha5 mAbs. Ser156-Trp157 is located near the apex of a putative loop region on the upper surface of a predicted beta-propeller structure formed by the NH2-terminal repeats of alpha5. Our findings suggest that this sequence forms part of the ligand-binding pocket of alpha5 beta1. Furthermore, as Ser156-Trp157 is unique to the alpha5 subunit, it may be responsible for the specific recognition of RRETAWA by alpha5 beta1.

Amino Acid Sequence↗
PubMed1998

Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis.

In addition to being T lymphocyte-driven, psoriasis may be due in part to abnormal integrin expression. Normal-appearing (uninvolved) skin from psoriatic patients was examined to determine whether altered fibronectin or its receptor expression is detectable before development of psoriatic lesions. In contrast to skin from normal subjects, we detect by immunofluorescence the abnormal presence of plasma fibronectin in the basal cell layer of the epidermis of psoriatic uninvolved skin. Furthermore, increased fibronectin exposure superinduces the in vitro cell cycle induction and expansion of psoriatic nonlesional keratinocytes in response to a cocktail of T cell lymphokines. Fibronectin alone also appeared to increase cell cycle entry among uninvolved but not normal keratinocytes. Concordantly, the alpha5 integrin fibronectin receptor, but not alpha2 or alpha3, is overexpressed in the in vivo nonlesional psoriatic epidermis. The involvement of alpha5beta1 in the early outgrowth of clonogenic keratinocytes in the ex vivo culture was demonstrated by the ability of anti-alpha5 mAb to inhibit keratinocyte growth on fibronectin. Thus, the fibronectin receptor appears to be one of the components required for the development of the hyperresponsiveness of psoriatic keratinocytes to signals for proliferation provided by lymphokines produced by intralesional T lymphocytes in psoriasis.

Antigens, CD↗
PubMed2002

The PDZ domain of TIP-2/GIPC interacts with the C-terminus of the integrin alpha5 and alpha6 subunits.

Different cDNA libraries were screened by the yeast two-hybrid system using as a bait the cytoplasmic sequence of integrin alpha6A or alpha6B subunits. Surprisingly, the same PDZ domain-containing protein, TIP-2/GIPC, was isolated with either of the variants, although their sequences are different. Direct interaction assays with the cytoplasmic domain of the integrin alpha1--7 subunits revealed that in addition to alpha6A and alpha6B, TIP-2/GIPC reacted also with alpha5, but not other alpha integrin subunits. The specificity of the interaction was confirmed by in vitro protein binding assays with purified peptides corresponding to integrin cytoplasmic domains. Further analysis with either truncation fragments of TIP-2/GIPC or mutated integrin cytoplasmic domains indicated that the interaction occurs between the PDZ domain of TIP-2/GIPC and a consensus PDZ domain-binding sequence, SDA, present at the C-terminus of the integrin alpha5 and alpha6A subunits. The integrin alpha6B subunit terminates with a different sequence, SYS, which may represent a new PDZ domain-binding motif.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Expression of the integrin alpha5 subunit and its mediated cell adhesion in hepatocellular carcinoma.

Tumor invasion and metastasis are complex processes, requiring the ability of tumor cells to interact with proteins of the extracellular matrix through cell-adhesion molecules on the cell surface. Integrins are heterodimeric membrane glycoproteins, consisting of alpha and beta subunits, which enable cells to recognize adhesive substrates in the extracellular matrix. The roles of the integrin alpha5beta1 in tumor invasion are highlighted by finding that some tumor cells have lost or reduced alpha5beta1 expression. It therefore functions as a negative signaling regulator. Expression of alpha5beta1 and its mediation of cell adhesion in hepatocellular carcinoma (HCC) have not been elucidated. In surgical specimens of HCC we found, by immunohistochemistry and Northern blot analysis, that the alpha5-positive rates in cancerous tissues were lower than the corresponding rates in non-cancerous tissues. Reduced expression of the integrin alpha5 occurred more frequently in HCC with more malignant phenotypes, such as poor differentiation, large size (more than 10-cm in diameter), absence of capsule and high invasion. Reverse transcription/polymerase chain reaction, a more sensitive assay, was used to detect the alpha5 mRNA level in LCID20, a highly metastatic model of human HCC, and LCID35, a low-metastasis model. The results showed that integrin alpha5 was negative in the former and positive in the latter. Cell adhesion assays showed the maximal percentage inhibition of anti-alpha5 mAb on SMMC 7721 cell adhesion to fibronectin to be 68.9 +/- 4.9% at the saturation concentrations of each antibody (200 microg/ml). If anti-alpha5 mAb was combined with anti-beta1 mAb, the inhibition was 74.1 +/- 11.1%. It is concluded that reduced expression of the integrin alpha5 subunit is correlated with more malignant phenotypes of human HCC. Any change in the adhesion of hepatocellular carcinoma cells to fibronectin is mainly dependent upon the function of the integrin alpha5beta1.

Antigens, CD↗
PubMed1999

CD9 is expressed in extravillous trophoblasts in association with integrin alpha3 and integrin alpha5.

The CD9 molecule is a 24-27 kDa cell surface glycoprotein, which may be related to Schwann cell migration and adhesion. In this study, we examined the expression of CD9 in human extravillous trophoblasts, which invade into the endometrium during implantation and placentation. CD9 was detected immunohistochemically on the extravillous trophoblasts in the cell columns of first trimester placentae, but not on villous trophoblasts. In the second and third trimester, CD9 was highly expressed on the extravillous trophoblasts in the basal plate of placentae, and in the chorion laeve in the fetal membrane of term placentae. The molecular mass of CD9 in the chorion laeve was shown to be 27 kDa by Western blotting. The mRNA of CD9 was also detected in the chorion laeve by reverse transcription-polymerase chain reaction (RT-PCR). Proteins were purified from chorion laeve by affinity chromatography with anti-integrin alpha3 and alpha5 monoclonal antibodies and Western blotting, revealed that CD9 was associated with both integrins. These findings indicate that CD9 is a differentiation-related molecule present in the extravillous trophoblasts. Since it is associated with integrin alpha5 which has been proposed to regulate trophoblast invasion, CD9 may be implicated in trophoblast invasion at the feto-maternal interface.

Antigens, CD↗
PubMed2001

Proteolysis of integrin alpha5 and beta1 subunits involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells.

Our previous report demonstrated that all-trans-retinoic acid (ATRA) induces detachment and death under serum starvation in several human tumor cell lines. In this study, we examined the influence of cell-extracellular matrix interaction on the ability of ATRA to induce apoptosis. Plating of human hepatoma Hep3B cells onto poly-hydroxyethylmethacrylate-coated plates in the absence of serum resulted in the acceleration of ATRA-induced apoptosis. In contrast, ATRA-induced apoptosis was significantly suppressed by plating cells onto Matrigel-coated plates but not suppressed by culturing onto collagen-, laminin-, vitronectin-, or fibronectin-coated plates. Exogenously added soluble collagen, laminin, fibronectin, vitronectin or Matrigel failed to suppress ATRA-induced apoptosis. Results from the adhesion assay indicated that the cell attachment to fibronectin was significantly inhibited by ATRA. Treatment with perturbing antibody against integrin alpha5 or beta1 subunits resulted in promotion of ATRA-induced apoptosis. Moreover, the proteolytic cleavage of alpha5beta1 integrin and focal adhesion kinase (FAK) proteins is linked to the early phase of the ATRA-induced apoptotic process. Furthermore, ATRA-induced detachment, death, and cleavage of alpha5beta1 integrin and FAK were drastically suppressed by plating cells onto Matrigel-coated plates. These findings provide evidence that abrogation of cell adhesion, through proteolysis of alpha5beta1 integrin and FAK, is closely linked to ATRA-induced apoptosis in Hep3B cells.

Antineoplastic Agents↗
PubMed1998

Regulation of integrin function: evidence that bivalent-cation-induced conformational changes lead to the unmasking of ligand-binding sites within integrin alpha5 beta1.

The molecular mechanisms that regulate integrin-ligand binding are unknown; however, bivalent cations are essential for integrin activity. According to recent models of integrin tertiary structure, sites involved in ligand recognition are located on the upper face of the seven-bladed beta-propeller formed by the N-terminal repeats of the alpha subunit and on the von Willebrand factor A-domain-like region of the beta subunit. The epitopes of function-altering monoclonal antibodies (mAbs) cluster in these regions of the alpha and beta subunits; hence these mAbs can be used as probes to detect changes in the exposure or shape of the ligand-binding sites. Bivalent cations were found to alter the apparent affinity of binding of the inhibitory anti-alpha5 mAbs JBS5 and 16, the inhibitory anti-beta1 mAb 13, and the stimulatory anti-beta1 mAb 12G10 to alpha5 beta1. Analysis of the binding of these mAbs to alpha5beta1 over a range of Mn2+, Mg2+ or Ca2+ concentrations demonstrated that there was a concordance between the ability of cations to elicit conformational changes and the ligand-binding potential of alpha5 beta1. Competitive ELISA experiments provided evidence that the domains of the alpha5 and beta1 subunits recognized by mAbs JBS5/16 and 13/12G10 are spatially close, and that the distance between these two domains is increased when alpha5 beta1 is occupied by bivalent cations. Taken together, our findings suggest that bivalent cations induce a conformational relaxation in the integrin that results in exposure of ligand-binding sites, and that these sites lie near an interface between the alpha subunit beta-propeller and the beta subunit putative A-domain.

Antibodies, Monoclonal↗
PubMed2005

Peroxisome proliferator-activated receptor-gamma ligands inhibit alpha5 integrin gene transcription in non-small cell lung carcinoma cells.

We previously showed that fibronectin stimulates the growth of non-small cell lung carcinoma (NSCLC) cells through integrin alpha5beta1-dependent signals. We also demonstrated that peroxisome proliferator-activated receptor (PPAR)gamma ligands inhibit lung carcinoma cell growth. Because alpha5beta1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPARgamma ligands on its expression. We found that PPARgamma ligands decreased mRNA and protein expression of the alpha5 subunit of the alpha5beta1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPARgamma ligands BRL 49653 and GW1929, but not PGJ(2), on alpha5 gene expression were reversed by GW9662, an antagonist of PPARgamma. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on alpha5. PPARgamma ligands also reduced alpha5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPARgamma ligands GW1929 and BRL49653 inhibited AP-1 DNA binding, whereas 15d-PGJ(2) inhibited Sp1 DNA binding; both effects were blocked by Erk antisense oligonucleotides. GW1929 partially blocked fibronectin-induced NSCLC cell growth, but did not affect cell growth induced by epidermal growth factor. These results suggest that PPARgamma ligands inhibit alpha5 expression in NSCLC through Erk-related signals.

Base Sequence↗
PubMed2001

Polarized distribution of alpha5 integrin in dendrites of hippocampal and cortical neurons.

The distribution of immunoreactivity for the alpha5 subunit of the fibronectin receptor was evaluated in adult rat brain with particular interest in the cellular localization of immunostaining in the hippocampal formation and neocortex. Beyond localization to neuronal perikarya and short dendritic fragments within most brain areas, alpha5 immunoreactivity (-ir) was particularly dense within primary apical dendrites of pyramidal cells in both hippocampus and neocortex and within the dendritic arbors of cerebellar Purkinje cells. In hippocampal and cortical pyramidal cells, immunostaining was clearly polarized: alpha5-ir was not detectable in basal dendrites in hippocampal neurons and was limited to proximal arbors or absent from basal dendrites in pyramidal cells in superficial and deep layers of neocortex. Beyond this, alpha5-ir was distributed within the dendritic ramifications of the dentate gyrus granule cells and within perikarya and dendrites of occasional nonpyramidal neurons. Developmental studies demonstrated that, in both hippocampus and neocortex, alpha5-ir appears first within perikarya and is distributed to dendrites during the second postnatal week. These results are in accord with the broad hypothesis that integrins contribute to apical-basal differences in dendrites and that the integrin fibronectin (alpha5beta1) receptor, in particular, contributes to some late developing features of dendritic structure or function.

Animals↗
PubMed1998

Cross-talk between insulin receptor and integrin alpha5 beta1 signaling pathways.

The ligation and clustering of cell surface alphabeta heterodimeric integrins enhances cell adhesion and initiates signaling pathways that regulate such processes as cell spreading, migration, differentiation, proliferation and apoptosis. Here we show that insulin treatment of Chinese hamster ovary cells expressing insulin receptors (CHO-T) markedly promotes cell adhesion onto a fibronectin matrix, but not onto bovine serum albumin or poly-lysine. Incubation of cells with a GRGDSP peptide that specifically binds integrins (but not the nonspecific GRADSP peptide) abolishes this insulin effect, as does the potent phosphoinositide 3-kinase (PI 3-kinase) inhibitor wortmannin. Moreover, a specific blocking monoclonal anti-alpha5beta1 integrin antibody, PB-1, blocks insulin-stimulated cell adhesion onto fibronectin. Conversely, activating alpha5beta1 integrins on CHO-T cells by adherence onto fibronectin markedly potentiates the action of insulin to enhance insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation. Activation of alpha5beta1 integrin also markedly potentiates the recruitment of p85-associated PI 3-kinase activity to IRS-1 in response to submaximal levels of insulin in CHO-T cells. These data indicate that insulin potently activates integrin alpha5beta1 mediated CHO-T cell adhesion, while integrin alpha5beta1 signaling in turn enhances insulin receptor kinase activity and formation of complexes containing IRS-1 and PI 3-kinase. These findings raise the hypothesis that insulin receptor and alpha5beta1 integrin signaling act synergistically to enhance cell adhesion.

Androstadienes↗
PubMed1998

The cation-binding domain from the alpha subunit of integrin alpha5 beta1 is a minimal domain for fibronectin recognition.

The cation-binding domain from the alpha subunit of human integrin alpha5beta1 was produced as a recombinant protein, alpha5-(229-448). This protein displays a well defined fold with a content of 30-35% alpha-helix and 20-25% beta-strand, based on circular dichroism. The binding of Ca2+ or Mg2+ to alpha5-(229-448) results in a biphasic conformational rearrangement consistent with the occurrence of two classes of cation-binding sites differing by their affinities. The two classes of sites are located in two conformationally independent lobes, as established by a parallel study of two recombinant half-domains (N- and C-terminal) that also adopt stable folds. Upon saturation with divalent cations, alpha5-(229-448) binds an Arg-Gly-Asp (RGD)-containing fibronectin ligand to form a 1:1 complex. Complex formation is associated with a specific conformational adaptation of the ligand, suggesting an induced fit mechanism. In contrast, neither of the half-domains is competent for ligand binding. The alpha5-(229-448)-fibronectin complex is dissociated in the presence of an RGD peptide, as well as of a simple carboxylic acid, suggesting that the RGD aspartyl carboxylate is an essential element that directly interacts with the alpha5 cation-binding domain.

Amino Acid Sequence↗
PubMed2002

Fibronectin fragments active in chondrocytic chondrolysis can be chemically cross-linked to the alpha5 integrin receptor subunit.

OBJECTIVE: To determine whether fibronectin fragments (Fn-f) known to enhance cartilage matrix degradation and to alter chondrocyte metabolism, bind on the chondrocyte cell surface close enough to the alpha(5)beta(1) fibronectin (Fn) receptor to be chemically cross-linked to it. DESIGN: Biotinylated Fn-fs were added to chondrocytes, followed by cross-linking with dithiobissulfosuccinimidyl propionate, and the resultant alpha(5) complexes trapped on to antialpha(5)-agarose. Adherent material was analysed by probing with avidin-HRP. In a more specific approach in which only proximal targets could be cross-linked, photoaffinity labeled Fn-fs or Fn were added to cells, the derivatives activated and the cross-linked material analysed. Interaction of biotinylated Fn-fs and Fn with insolubilized alpha(5)beta(1) receptor was also visualized and quantified. RESULTS: Biotinylated Fn-fs and Fn, but not a control of BSA, were cross-linked to alpha(5) protein in the presence of the propionate. Photoaffinity label Fn-f and Fn, but not BSA, were cross-linked to alpha(5) protein as well. Interaction was decreased by addition of an excess of unlabeled Fn-f or Fn. Fn-fs bound to alpha(5)beta(1)-agarose, although the affinity was 30-fold weaker and the stoichiometry 20-fold greater when the smallest Fn-f was compared to native Fn. CONCLUSIONS: These data are consistent with a role for the alpha(5) subunit in Fn-f activities and suggest that the Fn-fs bind proximal or directly to alpha(5) receptors. The weaker, higher stoichiometry interaction of Fn-fs with receptor suggests that fragmentation has allowed de novo interactions not possible in native Fn.

Animals↗
PubMed2002

Expression of focal adhesion kinase and alpha5 and beta1 integrins in carcinomas and its clinical significance.

AIM: To detect the expression pattern of FAK (focal adhesion kinase) and integrin alpha5 and beta1 subunits in different kinds of cancerous tissues and to study their correlation with clinicopathological data including tumor type, grade and lymph node status. METHODS: Using an immunohistochemical technique, we examined the expression of FAK and integrin and subunits in cancerous and noncancerous tissues obtained from 75 patients with gastric carcinomas, 21 colorectal carcinomas, 16 hepatocellular carcinomas, 20 uterocervical carcinomas, and 20 breast carcinomas. RESULTS: The staining of FAK was stronger in cancerous than in noncancerous areas. Enhanced expression of FAKwas detected in poor-differentiated carcinoma of the stomach and colorectum. Tumors with lymph node metastases had more FAK protein than those without metastases. In addition, the deeper the extent of tumor infiltration, the higher the FAK expression. The expression of integrin alpha5 and beta1 subunits was lower in cancerous areas than in noncancerous areas, but it was higher in well-differentiated cancerous tissues than in poor differentiated tissues. The relationship between the expression of integrin alpha5 and beta1 subunits and infiltration or metastasis was not significant. Cancerous tissues with stronger FAK expression (++ or +++) also had a higher expression of integrin alpha5 and beta1 subunits in the tumor and its unaffected margins. CONCLUSION: FAK is a better marker for carcinogenesis and the progression of cancer than integrin alpha5 and beta1 subunit, and it may be not only a transformation-linked enzyme but also a progression-linked enzyme.

Adult↗
PubMed2006

[Analysis of genes related to sensitivity to navalbine and docetaxel in 10 lung cancer cell lines].

OBJECTIVE: To analyze the drug-sensitivity-related genes to anti-tumor drugs navalbine (NVB) and docetaxel (Doc) in four SCLC and six NSCLC cell lines. METHODS: The sensitivity of 4 SCLC lines and 6 NSCLC lines to NVB and to Doc was determined with MTT test. The expression of 1291 anti-tumor drug sensitivity-related genes in the 10 cell lines was assayed by cDNA macroarray technique, and cluster analysis was performed to find the relationship between the results obtained by the above mentioned two measurements. RESULTS: (1) The anti-tumor effect of NVB on the 10 cell lines was apparently better than that of Doc. (2) The drug sensitivity-related genes in these 10 cell lines showed a more close positive correlation with Doc than that with NVB, whereas more genes showed negative correlation with NVB than that with Doc. But in 6 NSCLC cell lines, more genes showed the same positive or negative correlation with the two drugs. (3) 51 genes in the 10 cell lines showed correlation with Doc or NVB. 13 of them had negative correlation with Doc, 11 of them showed positive correlation. 24 of them showed negative correlation with NVB, 3 of them showed positive correlation. 67 genes in 6 NSCLC cell lines showed a correlation with sensitivity to Doc or NVB, among them 34 had negative correlation with Doc, 4 had positive correlation. 25 genes had negative correlation with NVB, 4 had positive correlation. (4) Rab 1, Rab 3, Rho B, Rho C, Rac 1, Rac 2, Gho GDI beta, CD44, integrin alpha5, integrin alpha6, integrin beta5, vinculin showed to be cytoskeleton-related genes differently expressing in SCLC or NSCLC cell lines. CONCLUSION: There is obvious difference in the drug sensitivity-related genes to NVB or Doc between SCLC and NSCLC cell lines.

Antineoplastic Agents↗
PubMed2000

Integrin alpha5/beta1 mediates fibronectin-dependent epithelial cell proliferation through epidermal growth factor receptor activation.

Human integrin alpha5 was transfected into the integrin alpha5/beta1-negative intestinal epithelial cell line Caco-2 to study EGF receptor (EGFR) and integrin alpha5/beta1 signaling interactions involved in epithelial cell proliferation. On uncoated or fibronectin-coated plastic, the integrin alpha5 and control (vector only) transfectants grew at similar rates. In the presence of the EGFR antagonistic mAb 225, the integrin alpha5 transfectants and controls were significantly growth inhibited on plastic. However, when cultured on fibronectin, the integrin alpha5 transfectants were not growth inhibited by mAb 225. The reversal of mAb 225-mediated growth inhibition on fibronectin for the integrin alpha5 transfectants correlated with activation of the EGFR, activation of MAPK, and expression of proliferating cell nuclear antigen. EGFR kinase activity was necessary for both MAPK activation and integrin alpha5/beta1-mediated cell proliferation. Although EGFR activation occurred when either the integrin alpha5-transfected or control cells were cultured on fibronectin, coprecipitation of the EGFR with SHC could be demonstrated only in the integrin alpha5-transfected cells. These results suggest that integrin alpha5/beta1 mediates fibronectin-induced epithelial cell proliferation through activation of the EGFR.

Antigens, CD↗