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Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell
Seiichi Ishida1, Yukari Shigemoto-Mogami, Youichi Shinozaki
1Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. ishida@nihs.go.jp
Abstract:
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 .
Insights
All-trans retinoic acid (ATRA) and Am80 differentially regulate gene expression during HL-60 cell differentiation. ATRA specifically suppresses PI3-kinase/Akt pathway genes, inhibiting proliferation.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- All-trans retinoic acid (ATRA) and Am80 are Vitamin A derivatives used in oncology and dermatology.
- Their mechanisms involve retinoic acid receptors (RARs), but distinct biological effects on cell proliferation and differentiation are observed.
- Differences in gene modulation between ATRA and Am80 in HL-60 cells remain unclear.
Purpose of the Study:
- To identify genes differentially modulated by ATRA and Am80 during HL-60 cell differentiation.
- To elucidate the molecular mechanisms underlying the distinct effects of ATRA and Am80 on cell proliferation and apoptosis.
- To investigate the role of the PI3-kinase/Akt pathway in ATRA and Am80-induced cellular responses.
Main Methods:
- Human promyelocytic leukemia (HL-60) cell differentiation induced by ATRA and Am80 over 72 hours.
- DNA microarray analysis to assess genome-wide gene expression changes.
- Clustering analysis to identify differentially expressed genes and pathways.
- Inhibition of PI3-kinase to evaluate its role in cell proliferation.
Main Results:
- Differential expression of 204 genes identified between ATRA and Am80 treatments.
- ATRA specifically suppressed the expression of phosphoinositide-3-kinase and ribosomal protein S6 kinase polypeptide 1 (PI3-kinase/Akt pathway).
- PI3-kinase inhibition mimicked ATRA's effect on suppressing Am80-treated cell proliferation, indicating pathway involvement.
Conclusions:
- Gene products within the PI3-kinase/Akt pathway are crucial for HL-60 cell growth suppression during late-stage differentiation.
- ATRA's antiproliferative effect is mediated, in part, by suppressing this pathway.
- Distinct gene modulation patterns by ATRA and Am80 contribute to their differential effects on HL-60 cell behavior.
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