Regulation of polyamine analogue cytotoxicity by c-Jun in human MDA-MB-435 cancer cells.
Several polyamine analogues have efficacy against a variety of epithelial tumor models including breast cancer. Recently, a novel class of polyamine analogues designated as oligoamines has been developed. Here, we demonstrate that several representative oligoamine compounds inhibit in vitro growth of human breast cancer MDA-MB-435 cells. The activator protein-1 (AP-1) transcriptional factor family members, c-Jun and c-Fos, are up-regulated by oligoamines in MDA-MB-435 cells, suggesting a possible AP-1-dependent induction of apoptosis. However, the use of a novel c-Jun NH(2)-terminal kinase (JNK) inhibitor, SP600125, suggests that inhibition of c-Jun activity sensitized tumor cells to oligoamine-induced cell death. To directly test this hypothesis, cells were stably transfected with the dominant-negative mutant c-Jun (TAM67), which lacks the NH(2)-terminal transactivation domain. Cells overexpressing TAM67 exhibit normal growth kinetics but demonstrate a significantly increased sensitivity to oligoamine cytotoxicity and attenuated colony formation after oligoamine treatment. Furthermore, oligoamine treatment leads to more profound caspase-3 activation and poly(ADP-ribose) polymerase cleavage in TAM67 transfectants, suggesting that c-Jun acts as an antiapoptosis factor in MDA-MB-435 cells in response to oligoamine treatment. These findings indicate that oligoamine-inducible AP-1 plays a prosurvival role in oligoamine-treated MDA-MB-435 cells and that JNK/AP-1 might be a potential target for enhancing the therapeutic efficacy of polyamine analogues in human breast cancer.
Huang
Yi
Y
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD and SLIL Biomedical Corp., Madison, WI, USA.
Keen
Judith C
JC
Hager
Erin
E
Smith
Renee
R
Hacker
Amy
A
Frydman
Benjamin
B
Valasinas
Aldonia L
AL
Reddy
Venodhar K
VK
Marton
Laurence J
LJ
Casero
Robert A
RA
Davidson
Nancy E
NE
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011073:Polyamines / Q000737:chemistry* / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000873:Anthracenes; D010446:Peptide Fragments; D011073:Polyamines; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; C432165:pyrazolanthrone