Abstract
BackgroundApoptosis caused by inadequate or inappropriate cell-matrix interactions is defined as anoikis. Although transformed cells are known to be anoikis-resistant, the underlying mechanisms have not been well understood. We investigated the mechanisms of anoikis resistance of tumor cells.ResultsWe observed that cell aggregation in suspension promoted cell survival and proliferation. We demonstrated a correlation between tumor cell aggregation in suspension and cell growth in soft agar. Analysis of tyrosine kinase-mediated cell survival and growth signaling pathways revealed increased levels of tyrosine-phosphorylation of PECAM-1 and Pyk2 in cell aggregates. We also showed that PECAM-1 and Pyk2 physically interact with each other, and that PECAM-1 carrying a deletion of exons 11-16 could no longer bind to Pyk2. Furthermore, RNA interference-mediated reduction of Pyk2 and PECAM-1 protein levels reduced cell aggregation and inhibited the growth of tumor cells in soft agar.ConclusionsThe data demonstrated that Pyk2 and PECAM-1 were critical mediators of both anchorage-independent growth and anoikis resistance in tumor cells.
Highlights
Apoptosis caused by inadequate or inappropriate cell-matrix interactions is defined as anoikis
The data demonstrated that Pyk2 and PECAM-1 were critical mediators of both anchorageindependent growth and anoikis resistance in tumor cells
We observed that these tumor cells often formed cell aggregates, and the size and tightness of the aggregates varied depending on the cell line used (Fig. 1A upper)
Summary
Apoptosis caused by inadequate or inappropriate cell-matrix interactions is defined as anoikis. Transformed cells are known to be anoikis-resistant, the underlying mechanisms have not been well understood. We investigated the mechanisms of anoikis resistance of tumor cells. In the absence of matrix attachment, these cells have been shown to undergo anoikis, a form of apoptosis [1]. Anoikis is important in maintaining normal cell and tissue homeostasis to ensure a dynamic balance of cell proliferation, differentiation, and apoptosis [2]. Previous studies have shown that tumor cells tend to form aggregates in the absence of matrix attachment. Tumor cells that formed aggregates in suspension cultures were found to exhibit significantly lower levels of apoptosis than single cells, indicating an increased resistance to anoikis.
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