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© The Rockefeller University Press, 0021-9525/1997//901 $5.00
The Journal of Cell Biology, Volume 138, Number 4, , 1997 901-911

Article

Loss of Matrix Adhesion Triggers Rapid Transformation-Selective Apoptosis in Fibroblasts



Gaël McGill*,{ddagger}, Akiko Shimamura*, Richard C. Bates*, Robert E. Savage{ddagger}, and David E. Fisher*

* Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and {ddagger} Department of Biology, Swarthmore College, Swarthmore, Pennsylvania 19081

Cell–matrix and cell–cell adhesion are recognized physiological determinants of cell growth and survival. In epithelial and endothelial cell systems, oncogenic transformation has in several cases been shown to confer resistance to apoptosis upon depriving cells of substrate adhesion. We examined the effects of oncogenic transformation in adherent versus adhesion- deprived primary embryonic fibroblasts. Whereas untransformed early passage fibroblasts undergo cell cycle arrest, their Myc/Ras- or E1A/Ras-transformed counterparts rapidly enter apoptosis when placed into suspension. This phenomenon also occurs upon incubation with a soluble, RGD-containing integrin ligand and is blocked by a peptide antagonist to ICE family proteases or by aggregation of cells plated at high density. Loss of wild-type p53 modulates the kinetics but does not abrogate this death pathway. Transformation with activated Src rather than Ras rendered fibroblasts selectively resistant to adhesion-dependent apoptosis, an effect likely related to Src's role in integrin signaling, while simultaneously sensitizing the cells to radiation-induced apoptosis. Thus cell adhesion events regulate transformation-selective apoptosis in fibroblasts and provide potentially important targets for understanding and interfering with tumor cell viability.

Abbreviations used in this paper: ECM, extracellular matrix; FAK, focal adhesion kinase; HUVEC, human umbilical vein endothelial cells; ICE, interleukin-1β converting enzyme; MEC, mammary epithelial cells; MEF, mouse embryo fibroblasts; PARP, polyADP ribose polymerase; REF, rat embryo fibroblasts; polyHEMA, polyhydroxyethylmethacrylate.

Please address all correspondence to David E. Fisher, Children's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Tel.: (617) 632-4916; Fax: (617) 632-2085.


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