Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells.
BACKGROUND
Chemoresistance is an important clinical problem in pancreatic cancer. As the mitogen-activated protein kinases (MAPKs) have been found to be involved in the development of chemoresistance in a variety of cancer cell lines, the aim of the current study was to assess the role and mechanism of MAPK signaling in mediating chemoresistance in pancreatic cancer cells.


METHODS
The effects of pharmacological inhibition of MAPKs on resistance of pancreatic cancer cells to apoptosis induced by treatment with chemotherapeutic drugs were analyzed.


RESULTS
Compared with parental cells, the activity of extracellular signal-regulated kinase (ERK) was elevated in all of the three chemoresistant sublines at basal conditions. Inhibition of the ERK pathway by PD98059 sensitized cells to 5-fluorouracil (5-FU), whereas cells became more resistant to Adriamycin (ADM; Meiji Seika, Tokyo, Japan) and gemcitabine (GEM). 5-FU induced apoptosis primarily via a caspase-8-dependent pathway, and ADM and GEM via caspase-9. PD98059 enhanced the activity of caspase-8 and inhibited the activation of caspase-9. In addition, PD98059 regulated the level of phospho-Bcl-2.


CONCLUSIONS
These data suggest that although constitutive activation of the ERK pathway might be a marker of chemoresistance, the effects of this pathway on chemoresistance of pancreatic cancer cells are drug dependent. This study also provides evidence for a possible link between the ERK pathway and activation of the caspases and Bcl-2.
Zhao
Yupei
Y
Department of General Surgery, Peking Union Medical College Hospital, Beijing, China. Zhao8028@263.net
Shen
Songjie
S
Guo
Junchao
J
Chen
Herbert
H
Greenblatt
David Yu
DY
Kleeff
Jörg
J
Liao
Quan
Q
Chen
Ge
G
Friess
Helmut
H
Leung
Po Sing
PS
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000093542:Gemcitabine
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005472:Fluorouracil; D000093542:Gemcitabine