ß3 integrin modulates transforming growth factor beta induced (TGFBI) function and paclitaxel response in ovarian cancer cells.
ABSTRACT The extracellular matrix (ECM) has a key role in facilitating the progression of ovarian cancer and we have shown recently that the secreted ECM protein TGFBI modulates the response of ovarian cancer to paclitaxel-induced cell death.
We have determined TGFBI signaling from the extracellular environment is preferential for the cell surface αvß3 integrin heterodimer, in contrast to periostin, a TGFBI paralogue, which signals primarily via a ß1 integrin-mediated pathway. We demonstrate that suppression of ß1 integrin expression, in ß3 integrin-expressing ovarian cancer cells, increases adhesion to rTGFBI. In addition, Syndecan-1 and -4 expression is dispensable for adhesion to rTGFBI and loss of Syndecan-1 cooperates with the loss of ß1 integrin to further enhance adhesion to rTGFBI. The RGD motif present in the carboxy-terminus of TGFBI is necessary, but not sufficient, for SKOV3 cell adhesion and is dispensable for adhesion of ovarian cancer cells lacking ß3 integrin expression. In contrast to TGFBI, the carboxy-terminus of periostin, lacking a RGD motif, is unable to support adhesion of ovarian cancer cells. Suppression of ß3 integrin in SKOV3 cells increases resistance to paclitaxel-induced cell death while suppression of ß1 integrin has no effect. Furthermore, suppression of TGFBI expression stimulates a paclitaxel resistant phenotype while suppression of fibronectin expression, which primarily signals through a ß1 integrin-mediated pathway, increases paclitaxel sensitivity.
Therefore, different ECM components use distinct signaling mechanisms in ovarian cancer cells and in particular, TGFBI preferentially interacts through a ß3 integrin receptor mediated mechanism to regulate the response of cells to paclitaxel-induced cell death.
Article: Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule.[show abstract] [hide abstract]
ABSTRACT: The ability of fibronectin to bind cells can be accounted for by the tetrapeptide L-arginyl-glycyl-L-aspartyl-L-serine, a sequence which is part of the cell attachment domain of fibronectin and present in at least five other proteins. This tetrapeptide may constitute a cellular recognition determinant common to several proteins.Nature 309(5963):30-3. · 36.28 Impact Factor
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ABSTRACT: To implement the proposed Clinton mental health benefit for the year 2001 requires a capacity to manage a flexible, comprehensive benefit. If fragmentation of services and discontinuity of care are to be reduced, mechanisms must be developed to coordinate services among domains--between acute and chronic care, and among public and private providers. Evidence exists that basic mental health services generally can be managed in health maintenance organizations (HMOs) with considerable cost savings and without detrimental effects on health, but it is less clear whether this is true of services for persons with severe and persistent mental illness. Effective services for persons with severe disorders require a capacity to organize and manage services across broad medical and social areas, but anticipated costs encourage providers to narrow the scope of care they offer and to select low-risk patients. Much will depend on developing methodologies that allow providers to be reimbursed accurately in relation to risk and that protect small providers from the potential cost of acquiring too many high-risk patients.Hospital & community psychiatry 10/1994; 45(9):893-7.