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J Biol Chem, Vol. 273, Issue 46, 30608-30613, November 13, 1998

c-Myc Is a Major Mediator of the Synergistic Growth Inhibitory Effects of Retinoic Acid and Interferon in Breast Cancer Cells

Yongfeng ShangDagger , Craig R. Baumrucker§, and Michael H. GreenDagger

From the Dagger  Nutrition Department and the § Department of Dairy and Animal Science, Pennsylvania State University, University Park, Pennsylvania 16802

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-alpha were investigated. All-trans-retinoic acid and interferon-alpha acted synergistically to inhibit growth of both the estrogen receptor-positive breast cancer cell line MCF-7 and the estrogen receptor-negative line BT-20. In MCF-7 cells, all-trans-retinoic acid potentiated the effects of interferon-alpha by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-alpha down-regulated the expression of c-Myc, but not its functional partner, Max. Transfection of MCF-7 cells with a dominant-negative mutant of PKR relieved c-Myc down-regulation and cell growth inhibition, indicating that PKR is directly involved in c-Myc down-regulation and that c-Myc down-regulation is responsible for the inhibition of cell growth. Corresponding with c-Myc down-regulation, c-Myc·Max heterodimers bound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-alpha , indicating diminished c-Myc functionality. When c-Myc was overexpressed ectopically via a c-Myc expression vector, MCF-7 cells became resistant to growth inhibition by all-trans-retinoic acid plus interferon-alpha . These experiments define the following pathway as a major pathway in the synergistic growth inhibition of MCF-7 cells by all-trans-retinoic acid plus interferon-alpha : all-trans-retinoic acid + interferon-alpha right-arrow up-arrow  double-stranded RNA-dependent protein kinase right-arrow down-arrow  c-Myc right-arrow cell growth inhibition.


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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