BACKGROUND: Anoikis is a special type of programmed cell death after loss of 
cell-cell and cell-extracellular matrix interactions. Resistance to anoikis is 
likely involved in the process of metastasis, specifically during the tumor cell 
migration through lymph or vascular channels. We have previously shown that 
BCL-2 confers resistance to other forms of programmed cell death (i.e., 
apoptosis); furthermore, the extracellular signaling-regulated kinase (ERK) 
signaling pathway regulates BCL-2 expression. We therefore tested the hypothesis 
that pancreatic cancer cell lines are resistant to anoikis and this resistance 
is due to activation of ERK1/2 and subsequent overexpression of BCL-2.
MATERIALS AND METHODS: Pancreatic cancer cell lines (MIA-PaCa-2 and BxPC-3) were 
examined for cell death following loss of adherence to extracellular matrix. 
Subclones of the MIA-PaCa-2 cell line (either selected in vivo for increased 
metastatic potential [MIA-LM2] or overexpressing BCL-2 [MIA-BCL2]) were also 
examined for induction of anoikis following loss of extracellular matrix 
adherence. Finally, the effect of the ERK inhibitor (PD98059) on BCL-2 
expression and induction of anoikis was examined.
RESULTS: Under conditions of loss of cell-extracellular matrix interaction, 
pancreatic cancer cells undergo varying amounts of anoikis. Basal levels of 
activated ERK and BCL-2 paralleled the sensitivity to induction of anoikis. The 
highly metastatic cell line, MIA-LM2, was more resistant to anoikis than the 
parental cell line. Inhibition of ERK down-regulated BCL-2 and was associated 
with restoration of sensitivity to anoikis.
CONCLUSIONS: Activation of a signaling pathway from ERK to overexpression of 
BCL-2 may confer resistance to anoikis, a critical step in the development of 
metastasis. Targeting the ERK/BCL-2 pathway may lead to sensitization of 
pancreatic cancer to anoikis, thereby decreasing the ability of these cells to 
metastasize.