Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis

Biochem Pharmacol. 2004 Dec 1;68(11):2177-86. doi: 10.1016/j.bcp.2004.08.017.


All-trans retinoic acid (ATRA) and Am80 are natural and synthetic derivatives of Vitamin A and have been used in the fields of oncology and dermatology for years. Their action was considered to be achieved mainly through binding to nuclear hormone receptors, retinoic acid receptors (RARs), although they have been observed to have different biological effects. For example, the two compounds have similar effects on differentiation but different effects on proliferation in human promyelocytic leukemia cell line HL-60 cells. To elucidate the genes responsible for this and other differences, we attempted for the first time to determine the genes whose expressions were differentially modulated during the time course of HL-60 cell differentiation by ATRA and Am80 treatment up to 72h utilizing DNA microarray and clustering analyses. As a result, the expressions of 204 genes were found to be modulated differentially by ATRA and Am80. Among them, we focused on two components of the PI3-kinase/Akt signal transduction pathway, phosphoinositide-3-kinase, beta-catalytic subunit and ribosomal protein S6 kinase polypeptide 1, which are related to the regulation of cell proliferation and apoptosis. Their expressions were specifically suppressed by ATRA, which coincided with the suppressive effects of ATRA on the HL-60 cell proliferation. Moreover, PI3-kinase inhibitors suppressed the proliferation of Am80-treated cells to the same extent as ATRA did. These results indicated that these gene products play a role in HL-60 cell growth suppression during the late stage of differentiation. The complete data and a list of the genes are available at .

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Benzoates / pharmacology*
  • Carrier Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Gene Expression Profiling
  • HL-60 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Tetrahydronaphthalenes / pharmacology*
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Benzoates
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Tetrahydronaphthalenes
  • tamibarotene
  • Tretinoin
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • RPS6KC1 protein, human
  • Ribosomal Protein S6 Kinases