c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells

Yongfeng Shang, Craig R. Baumrucker, Michael H. Green

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-α were investigated. All- trans-retinoic acid and interferon-α 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-α by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-α 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 hound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-α, 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- α. 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-α: all-trans-retinoic acid + interferon-α → double-stranded RNA-dependent protein kinase → ↓ c-Myc → cell growth inhibition.

Original languageEnglish (US)
Pages (from-to)30608-30613
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number46
DOIs
StatePublished - Nov 13 1998

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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