Abstract
Ataxia telangiectasia mutated (ATM) kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR). The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15) and Chk1 (Ser317) was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins / metabolism*
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Cell Cycle / drug effects
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Cell Cycle / radiation effects
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / radiation effects
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Checkpoint Kinase 1
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DNA Damage / drug effects*
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DNA Damage / radiation effects
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Gamma Rays
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HEK293 Cells
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Humans
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation / drug effects
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Phosphorylation / radiation effects
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Protein Kinases / metabolism
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Protein Phosphatase 2C
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Signal Transduction / drug effects*
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Signal Transduction / radiation effects
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Squalene / pharmacology*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Cell Cycle Proteins
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Tumor Suppressor Protein p53
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Squalene
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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PPM1D protein, human
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Phosphoprotein Phosphatases
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Protein Phosphatase 2C
Grants and funding
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant No. 24580203) to HN, Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities (Grant No. S1001030) to HN and TK, and JSPS KAKENHI (Grant No. 25293029) to HN and Masaji Ishiguro, Niigata. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.