Functional dissociation of anoikis-like cell death and activity of stress activated protein kinase

Adhesion to the extracellular matrix is a crucial survival signal for epithelial and endothelial cells. Both cell types activate an endogenous death program termed "anoikis" when detached from the solid substratum. The signaling events culminating in anoikis are still unclear; recent studies have implicated Stress Activated Protein Kinase (SAPK), also known as Jun-N-Terminal kinase, as a potentially crucial signal transducer and mediator of anoikis. However, the generality and the causal role of SAPK in anoikis remain unclear and controversial. For these reasons we decided to examine the relationship between induction of anoikis and SAPK activation in three independent cell systems. We report here that in immortalized rat intestinal epithelial cells (IEC-18) and human umbilical vein endothelial cells (HUVEC), SAPK is activated weakly and transiently upon cell detachment while in canine kidney epithelial cells (MDCK) such induction is strong and protracted. However, cell types fail to commit to anoikis after remaining in three-dimensional culture for the time required for complete activation of SAPK. This suggests that there is no temporal correlation between SAPK activation and the onset of anoikis in any of the cell lines studied. We further examined the potential involvement of SAPK in the IEC-18 system by investigating a ras oncogene-transformed variant of IEC-18 cells (IEC-18 Ras 3) which are highly resistant to anoikis. Ras expression did not abrogate activation of SAPK, although these cells do exhibit altered kinetics of SAPK induction upon cell detachment. These results suggest that SAPK is not involved in anoikis regulation and that SAPK activation is likely a cell-type-specific epi-phenomenon.