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 epith elial and endothelial cells. Both cell types activate an endogenous death p rogram termed "anoikis" when detached from the solid substratum. The signal ing events culminating in anoikis are still unclear; recent studies have im plicated Stress Activated Protein Kinase (SAPK), also known as Jun-N-Termin al kinase, as a potentially crucial signal transducer and mediator of anoik is. However, the generality and the causal role of SAPK in anoikis remain u nclear and controversial. For these reasons we decided to examine the relat ionship between induction of anoikis and SAPK activation in three independe nt cell systems. We report here that in immortalized rat intestinal epithel ial cells (IEC-18) and human umbilical vein endothelial cells (HUVEC), SAPK is activated weakly and transiently upon cell detachment while in canine k idney epithelial cells (MDCK) such induction is strong and protracted. Howe ver, cell types fail to commit to anoikis after remaining in three-dimensio nal culture for the time required for complete activation of SAPK. This sug gests 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 highl y resistant to anoikis. Pas expression did not abrogate activation of SAPK, although these cells do exhibit altered kinetics of SAPK induction upon ce ll detachment. These results suggest that SAPK is not involved in anoikis r egulation and that SAPK activation is likely a cell-type-specific epi-pheno menon. (C) 1999 Academic Press.