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

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          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.

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          Author and article information

          Journal
          Leuk. Res.
          Leukemia research
          Elsevier BV
          1873-5835
          0145-2126
          January 2018
          : 64
          Affiliations
          [1 ] Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo 156-8550, Japan. Electronic address: s.miya0024@mbr.nifty.com.
          [2 ] College of Life Science and Oceanography, Shenzhen University, Shenzhen 518060, China.
          [3 ] School of Pharmacy, Nihon University, Chiba 274-8555, Japan.
          Article
          S0145-2126(17)30488-5
          10.1016/j.leukres.2017.08.007
          29179029
          9f8a0b5a-bda5-4d28-af9a-a32c5b95280b
          History

          PTEN/Akt,Nuclear akt,ATM/ATR,Apoptosis,Cyclin D1 overexpression,Topo catalytic inhibitor

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