c-Jun N-terminal kinase regulates apoptosis in endometrial cancer cells.
c-Jun N-terminal kinases (JNKs) are important regulators of cell proliferation and apoptosis that have been implicated in tumorigenesis. We investigated the role of JNKs in apoptotic responses in Ishikawa and HEC-50 cells, models of type I and type II endometrial cancer, respectively. Etoposide treatment or UV irradiation resulted in sustained activation of JNK, correlating with the induction of apoptosis. Inhibition of JNK, or MAP kinase kinase 4 (MKK4), selectively suppressed apoptotic responses in both Ishikawa and HEC-50 cells. Knockdown of protein kinase C delta (PKCdelta) also attenuated apoptosis in endometrial cancer cells and inhibited the sustained, UV-mediated JNK activation in HEC-50, but not Ishikawa cells. Etoposide-induced JNK phosphorylation was unaffected by PKCdelta knockdown, implying that JNK can regulate apoptosis by PKCdelta-dependent and independent pathways, according to stimulus and cell type. Thus, expression and activity of JNK and PKCdelta in endometrial cancer cells modulate apoptosis and sensitivity to chemotherapeutic agents and may function as tumor suppressors in the endometrium.
Department of Obstetrics and Gynecology, Section of Basic Reproductive Sciences, School of Medicine, University of Colorado Denver, Mail Stop 8309, 12800 E. 19th Avenue, Aurora, CO 80045, USA.
Elaine M
EM
Reno
James M
JM
Haughian
Twila A
TA
Jackson
Alicia M
AM
Thorne
Andrew P
AP
Bradford
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D005047:Etoposide; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases