Regulation of Polyamine Analogue Cytotoxicity by c-Jun in Human MDA-MB-435 Cancer Cells
| Autor: | Yi Huang, Judith Keen, Erin Hager, Renee Smith, Amy Hacker, Benjamin Frydman, Valasinas, Aldonia L., Reddy, Venodhar K., Marton, Laurence J., Casero, Robert A., Davidson, Nancy E. |
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| Rok vydání: | 2004 |
| Předmět: | |
| Zdroj: | Dimensions |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | 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 NH2-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 NH2-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. |
| Databáze: | OpenAIRE |
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