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J. Biol. Chem., Vol. 278, Issue 50, 50402-50411, December 12, 2003
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Fibronectin Protects Prostate Cancer Cells from Tumor Necrosis Factor-
-induced Apoptosis via the AKT/Survivin Pathway*
¶
From the
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510
Integrins are cell surface heterodimeric transmembrane receptors that, in addition to mediating cell adhesion to extracellular matrix proteins modulate cell survival. This mechanism may be exploited in cancer where evasion from apoptosis invariably contributes to cellular transformation. The molecular mechanisms responsible for matrix-induced survival signals begin to be elucidated. Here we report that the inhibitor of apoptosis survivin is expressed in vitro in human prostate cell lines with the highest levels present in aggressive prostate cancer cells such as PC3 and LNCaP-LN3 as well as in vivo in prostatic adenocarcinoma. We also show that interference with survivin in PC3 prostate cancer cells using a Cys84
Ala dominant negative mutant or survivin antisense cDNA causes nuclear fragmentation, hypodiploidy, cleavage of a 32-kDa proform caspase-3 to active caspase-3, and proteolysis of the caspase substrate poly(ADP-ribose) polymerase. We demonstrate that in the aggressive PC3 cell line, adhesion to fibronectin via 
1 integrins results in up-regulation of survivin and protection from apoptosis induced by tumor necrosis factor-
(TNF-). In contrast, survivin is not up-regulated by cell adhesion in the non-tumorigenic LNCaP cell line. Dominant negative survivin counteracts the ability of fibronectin to protect cells from undergoing apoptosis, whereas wild-type survivin protects non-adherent cells from TNF--induced apoptosis. Evidence is provided that expression of 1A integrin is necessary to protect non-adherent cells transduced with survivin from TNF--induced apoptosis. In contrast, the 1C integrin, which contains a variant cytoplasmic domain, is not able to prevent apoptosis induced by TNF- in non-adherent cells transduced with survivin. Finally, we show that regulation of survivin levels by integrins are mediated by protein kinase B/AKT. These findings indicate that survivin is required to maintain a critical anti-apoptotic threshold in prostate cancer cells and identify integrin signaling as a crucial survival pathway against death receptor-mediated apoptosis.
Received for publication, July 15, 2003 , and in revised form, September 23, 2003.
* This work was supported in part by National Institutes of Health Grants R29 CA71870 and RO1 CA89720 (to L. R. L.) and RO1 CA78810, CA90917, and HL54131 (to D. C. A.) and by Department of Defense, Prostate Cancer Research Program, Grant DAMD17-98-1-8506 (to L. R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed: Dept. of Cancer Biology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-1606; Fax: 508-856-3845; E-mail: lucia.languino{at}umassmed.edu.
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