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Gynecol Oncol. 2002 May;85(2):339-50.

Caspase 3-mediated focal adhesion kinase processing in human ovarian cancer cells: possible regulation by X-linked inhibitor of apoptosis protein.

Author information

1
Reproductive Biology Unit, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9.

Abstract

OBJECTIVE:

Cell adhesion is an important cell survival determinant and disruption of integrin-mediated signal transduction may be involved in anchorage-dependent cell death. We have examined the processing of focal adhesion kinase (FAK), a component of integrin-mediated signal transduction, in a cisplatin-sensitive human ovarian epithelial cancer cell line (OV2008), to test the possible role of FAK degradation in the control of apoptosis via regulation of cell attachment.

METHODS:

FAK processing after cisplatin treatment in the absence or presence of various caspase-inhibiting substances was analyzed by Western blot. Caspase-inhibiting activities were introduced using cell-permeable peptides or adenoviral vector.

RESULTS:

Cisplatin-induced caspase 3 and FAK cleavage, cell detachment from the growth surface, and apoptosis in a temporally related and concentration-dependent manner. FAK fragments were detected exclusively in cells detached from the culture surface. Addition of active caspase 3 to the whole cell lysate elicited a similar pattern of FAK cleavage. Pretreatment of whole cell lysates and cells with tetrapeptide inhibitors of caspases significantly decreased FAK cleavage induced by exogenous active caspase 3 and cisplatin, respectively. Overexpression of X-linked inhibitor of apoptosis protein (Xiap), an endogenous caspase inhibitor, attenuated the cisplatin-induced FAK processing, morphologic changes, and apoptosis. The inhibitory action of Xiap was abolished with the deletion of a functional motif required for caspase inhibition.

CONCLUSION:

These findings are consistent with our hypothesis that FAK processing is in part mediated by caspase 3, the activation of which is modulated by Xiap.

PMID:
11972398
DOI:
10.1006/gyno.2002.6632
[Indexed for MEDLINE]

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