BMI1 Inhibitors Down-regulate NOTCH Signaling and Suppress Proliferation of Acute Leukemia Cells.

Abstract

BACKGROUND/AIM:

B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells.

MATERIALS AND METHODS:

Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting.

RESULTS:

PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis.Artemisinin acted only on Jurkat cells. BMI1 inhibitors and BMI1-specific siRNA down-regulated the expression of NOTCH signaling proteins NOTCH1, HES1, and MYC. All but one cell lines did not have the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene targeted by BMI1, thus the inhibitors acted through CDKN2A-independent pathways.

CONCLUSION:

BMI1 inhibition suppressed proliferation of leukemia cells through NOTCH signaling which functions downstream of BMI1, suggesting that BMI1 inhibitors can be candidate targeted drugs against leukemia.

• Authors: Mika Ohtaka, Mai Itoh, Shuji Tohda
• Journal: Anticancer research (Anticancer Res) Vol. 37 Issue 11 Pg. 6047-6053 (11 2017) ISSN: 1791-7530 [Electronic] Greece
• PMID: 29061784 (Publication Type: Journal Article)
• Copyright: Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• BMI1 protein, human
• Heterocyclic Compounds, 2-Ring
• PTC-209
• RNA, Small Interfering
• Receptors, Notch
• Thiazoles
• Polycomb Repressive Complex 1

Topics

• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 2-Ring (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Leukemia, T-Cell (drug therapy, metabolism, pathology)
• Polycomb Repressive Complex 1 (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Receptors, Notch (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)
• Tumor Cells, Cultured