MEK/ERK Signaling Pathway Regulates the Expression of Bcl-2, Bcl-X(L), and Mcl-1 and Promotes Survival of Human Pancreatic Cancer Cells

J Cell Biochem. 2000 Sep 7;79(3):355-69.

Abstract

Background and aims: Growth factors are well known for their participation in the regulation of cell proliferation and survival. However, the intracellular 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 of ERK1/2 activities in the regulation of cell survival and investigated some of the mechanisms involved.

Methods: The ability of the MEK inhibitor PD98059 to modulate survival of the MIA PaCa-2 cells was evaluated, and the responses were correlated with expression of Bcl-2 homologs and caspases 1, 3, 6, 8, and 9 activities.

Results: Herein, we showed that inhibition of ERK1/2 activities caused (1) a G1 arrest; (2) a down-regulation of the expression 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 caspases 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 activation of the ERK pathway functions to protect pancreatic tumor cells from apoptosis as well as to regulate their progression in the cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Caspases / biosynthesis
  • Caspases / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Survival
  • Cysteine Endopeptidases / physiology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology*
  • G1 Phase / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / physiology*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology*
  • Multienzyme Complexes / physiology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostaglandin-Endoperoxide Synthases / physiology
  • Proteasome Endopeptidase Complex
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Pyridines / pharmacology
  • Tumor Cells, Cultured / drug effects
  • bcl-X Protein

Substances

  • BCL2L1 protein, human
  • Cysteine Proteinase Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Multienzyme Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • bcl-X Protein
  • Prostaglandin-Endoperoxide Synthases
  • Poly(ADP-ribose) Polymerases
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Caspases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one