Nuclear retinoid receptors are involved in N-(4-hydroxyphenyl) retinamide (Fenretinide)-induced gene expression and growth inhibition in HL-60 acute myeloid leukemia cells

Bulent Ozpolat, Ana M. Tari, Kapil Mehta, Gabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

N-(4-hydroxyphenyl) retinamide (Fenretinide, 4-HPR) inhibits cell growth by inducing apoptosis in numerous tumor cell types including all-trans-retinoic acid (ATRA)-resistant tumor cells. However, the mechanism(s) by which 4-HPR mediates its anti-proliferative effects remains unclear. Here, we determined whether 4-HPR induced growth inhibition and gene expression involve retinoid receptors in human acute myeloid leukemia (AML) cells (HL-60). We treated HL-60 and ATRA-resistant HL-60 (HL-60R) cells that express mutated RARα and very low levels of RARβ, RARγ and RXRα with 4-HPR (2 μM) for 3 days. 4-HPR showed significant anti-proliferative effects against both cell types and induced growth inhibition (92.7%) in HL-60 cells. However, at the same dose, 4-HPR induced only 53.4% growth inhibition in HL-60R cells. Growth inhibition by 4-HPR was significantly enhanced in HL-60R cells that were retroviraly transduced to express human RARα, RARβ or RXRα (95.6%, 97.1%, and 75.6%, respectively), in comparison to HL-60R cells (P < 0.05), but not in HL-60R cells expressing RARγ. Although ATRA and 4-HPR induced expression of CYP26, an ATRA-inducible gene encoding a cytochrome P450 enzyme, in HL-60 cells, both retinoids failed to induce CYP26 in HL-60R cells. However, induction of CYP26 mRNA by 4-HPR was restored in HL-60R cells expressing RARα and RARγ, but not RARβ and RXRα. In conclusion, our data suggest that nuclear retinoid receptors are involved in 4-HPR-induced growth inhibition and gene expression, and that 4-HPR can mediate its anti-proliferative effects through retinoid receptor-dependent mechanisms in HL-60 cells.

Original languageEnglish (US)
Pages (from-to)979-985
Number of pages7
JournalLeukemia and Lymphoma
Volume45
Issue number5
DOIs
StatePublished - May 2004

Keywords

  • 4-HPR
  • CYP26
  • Fenretinide
  • Gene expression
  • Growth inhibition
  • Myeloid leukemia
  • Retinoid receptors

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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