Abstract
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.
Highlights
Adhesion to the extracellular matrix (ECM)1 is a process largely mediated by the integrin family of cell surface receptors, which modulates a number of pivotal cellular decisions ranging from embryonic development and differentiation to tumor cell growth and metastasis (Yamada and Miyamoto, 1995; Ruoslahti, 1996)
This behavior was observed in Myc-transformed Rat1 fibroblasts (Fig. 1 B), an oncogene/apoptosis system that has been extensively studied for apoptosis upon growth factor withdrawal (Askew et al, 1991; Evan et al, 1991; Wagner et al, 1994)
Preventing ECM adhesion of fibroblasts transformed by Myc and Ras or E1A and Ras leads to rapid cell death by apoptosis
Summary
Adhesion to the extracellular matrix (ECM) is a process largely mediated by the integrin family of cell surface receptors, which modulates a number of pivotal cellular decisions ranging from embryonic development and differentiation to tumor cell growth and metastasis (Yamada and Miyamoto, 1995; Ruoslahti, 1996). Primary cells of epithelial and endothelial origin rapidly undergo apoptosis when denied proper substrate adhesion in a process called anoikis (Frisch and Francis, 1994; Ruoslahti and Reed, 1994). Focal adhesion kinase (FAK), which is known to bind and mediate integrin-dependent signals (Schaller et al, 1992), has been shown to be required for the survival of both primary (Hungerford et al, 1996) as well as tumor cells (Xu et al, 1996) in the process of adhesion. The Journal of Cell Biology, Volume 138, Number 4, August 25, 1997 901–911 http://www.jcb.org chorage-independent growth potential of epithelial and endothelial cells that have lost substrate attachment (Ruoslahti and Reed, 1994)
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