3EZ, 20Ac-ingenol induces cell-specific apoptosis in cyclin D1 over-expression through the activation of ATR and downregulation of p-Akt. (January 2018)

• Record Type: Journal Article
• Authors: Miyata, Shohei; Wang, Li-Yan; Kitanaka, Susumu
• Is Part Of: Leukemia research. Volume 64(2018)
• Page Start: 46
• Page End: 51
• Publication Date: 2018-01
• Subjects: Topo catalytic inhibitor -- ATM/ATR -- PTEN/Akt -- Nuclear akt -- Cyclin D1 overexpression -- Apoptosis; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2017.08.007
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: DNA damage response (DDR) by 3EZ, 20Ac-ingenol is dependent on ATR expression. Nuclear p-Akt is reduced in BALL-1 cells which are arrested by 3EZ, 20Ac-ingenol. Increase of p-PTEN and PTEN by the DDR produces to reduce nuclear p-Akt. BALL-1 cells over-expressing cyclin D1 trigger intra S-phase checkpoint response. 3EZ, 20Ac-ingenol induces the specific DDR to cells overexpressing cyclin D1. Abstract: Acute lymphoblastic leukemia (ALL) samples exhibit an activated PI3K/Akt pathway, which suggests a general role of Akt in the development of leukemia. We have previously used western blot analysis to show that the catalytic topoisomerase (topo) inhibitor, 3EZ, 20Ac-ingenol, induced DNA damage response (DDR), which activated ATR, downregulated p-Akt through upregulation of PTEN level, and led to cell cycle arrest or apoptosis. In this study, we used ATR or PTEN siRNA and observed that the specific cell arrest and apoptosis of BALL-1 cells in DDR caused by 3EZ, 20Ac-ingenol was dependant on activation of ATR and downregulation of nuclear p-Akt through upregulation of PTEN. Moreover, some B cell lymphomas among ALLs overexpress cyclin D1. The DDR induced during the S-phase with 3EZ, 20Ac-ingenol treatment was increased by the intra S-phase checkpoint response that was triggered by the loss of nuclear cyclin D1 regulation in BALL-1 cells overexpressing cyclin D1. Although topo 1 catalytic inhibitors induce a decatenation checkpoint and subsequent G2/M phase arrest, the decatenation checkpoint caused by 3EZ, 20Ac-ingenol induced apoptosis only in the BALL-1 cells that accumulated cyclin D1.