Expression of adhesion receptor integrin ␣v3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that ␣v3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated ␣v3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated ␣v3. When transferred, this factor also up-regulated ␣v3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated ␣v3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced ␣v3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin ␣v3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated ␣v3.M etastasis is the primary cause of death in breast cancer patients. Metastatic dissemination depends on tumor cell adhesion, migration, and invasion. These steps involve integrins, a family of transmembrane adhesion receptors, composed of noncovalently linked ␣ and  subunits (1). Integrins are known to exist in distinct states of activation, and these determine integrin functionality and affinity for ligands (2). For example, integrin activation controls which ligands are recognized, whether an integrin can support cell arrest under dynamic flow conditions or only stationary adhesion, and whether cells can migrate on or toward specific substrates (3). The importance of integrin activation has long been appreciated in leukocytes and platelets, where it controls inflammatory responses and thrombus formation (4, 5). Recent findings indicate that other cell types, such as endothelial cells and tumor cells, can also regulate their interaction with extracellular matrix proteins by integrin activation (6-9). This regulation may help to control angiogenesis and tumor metastasis.In breast and ovarian cancer, as well as in melanoma and glioma, malignant progression is associated with expression of tumor cell integrin ␣v3 (10-14). We recently found that ␣v3 can exist in human breast cancer cells in an activated or a nonactivated functional state. Only the activated state supports breast cancer cell arrest du...
Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.
Since the mechanism of the antidepressant activity of hypericum extract is not yet understood, we tested possible effects of standardized hypericum extract (LI 160) in several biochemical models relevant for the mechanism of action of other antidepressant drugs. While LI 160 was only a weak inhibitor of MAO-A and MAO-B activity, it inhibited the synaptosomal uptake of serotonin, dopamine and norepinephrine with about equal affinity-2 micrograms/ml). Moreover, subchronic treatment of rats with hypericum extract led to a significant down-regulation of beta-receptors and to a significant up-regulation of 5-HT2-receptors in the frontal cortex. The data might suggest that hypericum extract acts via similar biochemical mechanisms to other antidepressants (e.g. tricyclics).
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