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p53 promotes AKT and SP1-dependent metabolism through the pentose phosphate pathway that inhibits apoptosis in response to nutlin-3a

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Journal of Molecular Cell Biology 2018年第4期10卷 331-340页

作者： Text Lei Duan Ricardo E. Perez Ling Chen Lothar A. Blatter Carl G. Maki Department of Cell & Molecular Medicine Rush University Medical Center Chicago IL 60612 USA Department of Laboratory Medicine Shiyan Taihe Hospital College of Biomedical Engineering Hubei University of Medicine Shiyan 442000 China Department of Physiology & Biophysics Rush University Medical Center Chicago IL 60612 USA

nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway （PPP） produces NADPH that can protect cells from potentially lethal reactive oxygen species （ROS）. We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with nutlin-3a. Apoptosis in MDM2-amplified cells was associated with a reduction in glycolysis and the PPP, reduced NADPH, increased ROS, and depletion of the transcription factor SP1, which normally promotes PPP gene expression. In contrast, glycolysis and the PPP were maintained or increased in MDM2 non-amplified cells treated with nutlin-3a. This was dependent on p53-mediated AKT activation and was associated with maintenance of SP1 and continued expression of PPP genes. Knockdown or inhibition of AKT, SP1, or the PPP sensitized MDM2-non-amplified cells to apoptosis. The data indicate that p53 promotes AKT and SP1-dependent activation of the PPP that protects cells from nutlin-3a-induced apoptosis. These findings provide insight into how glucose metabolism reduces nutlin-3a-induced apoptosis, and also provide a mechanism for the heightened sensitivity of MDM2-amplified cells to apoptosis in response to nutlin-3a.

关键词： nutlin p53 MDM2 SP1 glycolysis pentose phosphate pathway

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Design,Synthesis,and Biological Evaluation of Imidazoline Derivatives as p53-MDM2 Binding Inhibitors

Design,Synthesis,and Biological Evaluation of Imidazoline De...

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2011年全国药物化学学术会议——药物的源头创新

作者： Chunqi Hu,Yongzhou Hu~* ZJU-ENS Joint Laboratory of Medicinal Chemistry,Zhejiang University,Zijingang Campus,Hangzhou 310058,China

＜正＞The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in *** recent years,the activation by antagonizing the negative regulator of p53-MDM2（murine double minute 2,or HDM2 for the human congener） offers a new therapeutic *** series of 25 novel imidazoline derivatives were designed,synthesized

关键词： p53-MDM2 binding inhibitor nutlin anti-cancer

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