MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X-L, and Mcl-1 and promotes survival of human pancreatic cancer cells

Background and aims: Growth factors are well known for their participation in the regulation of cell proliferation and survival. However, the intracel lular signaling pathways by which growth factors promote survival are still poorly understood. In the present study, using the MIA PaCa-2 cell line, a well-established model of pancreatic cancer cells, we analyzed the roles o f ERK1/2 activities in the regulation of cell survival and investigated som e of the mechanisms involved. Methods: The ability of the MEK inhibitor PD9 8059 to modulate survival of the MIA PaCa-2 cells was Evaluated, and the re sponses were correlated with expression of Bcl-2 homologs and caspases 1, 3 , 6, 8, and 9 activities. Results. Herein, we showed that inhibition of ERK 1/2 activities caused (1) a G1 arrest; (2) a down-regulation of the express ion levels of the anti-apoptotic homologs Bcl-2, Mcl-1, and Bcl-X-L without affecting the pro-apoptotic levels of Bax and Bak; (3) a promotion of casp ases 3, 6, 8, and 9 activities; (4) a stimulation of PARP cleavage; and (5) a programmed cell death by apoptosis. Conclusion: Our data suggest that ac tivation of the ERK pathway functions to protect pancreatic tumor cells fro m apoptosis as well as to regulate their progression in the cell cycle. (C) 2000 Wiley-Liss, Inc.