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P53-regulated autophagy and its impact on drug resistance and cell fate

Cancer Drug Resistance 2021年第1期4卷 85-95页

作者： Daeun Shim Lei Duan carl g.maki Department of Cell and Molecular Medicine Rush University Medical CenterChicagoIL 60612USA

Wild-type p53 is a stress-responsive transcription factor and a potent tumor suppressor.P53 inhibits the growth of incipient cancer cells by blocking their proliferation or inducing their death through *** is a self-eating process that plays a key role in response to *** autophagy,organelles and other intracellular components are degraded in autophagolysosomes and the autophagic breakdown products are recycled into metabolic and energy producing pathways needed for survival.P53 can promote or inhibit autophagy depending on its subcellular localization,mutation status,and the level of *** autophagy has been reported in several studies to increase p53-mediated apoptosis,revealing that autophagy can influence cell-fate in response to activated p53 and is a potential target to increase p53-dependent tumor suppression.

关键词： Autophagy histone methylation metabolism

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Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells

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Journal of Molecular Cell Biology 2021年第6期13卷 433-444页

作者： Lei Duan Sarah Calhoun Daeun Shim Ricardo E.Perez Lothar A.Blatter carl g.maki Department of Cell and Molecular Medicine Rush University Medical CenterChicagoIL 60612USA Department of Molecular Biophysics and Physiology Rush University Medical CenterChicagoIL 60612USA

Tamoxifen(TAM)is the first-line endocrine therapy for estrogen receptor-positive(ER+)breast cancer(BC).However,acquired resistance occurs in∼50%***,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this ***,we analyzed signaling pathways and metabolism in ER+MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF *** found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant ***,ERRα/PgC-1βand their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation(FAO)and autophagy in TAM-resistant *** of AKT feedback-activates AMPK and ERRα/PgC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT ***,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant *** inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

关键词： endoxifen fatty acid oxidation autophagy AMPK AKT

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Erratum: P53-regulated autophagy and its impact on drug resistance and cell fate

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Cancer Drug Resistance 2021年第4期4卷 903-903页

作者： Daeun Shim Lei Duan carl g.maki Department of Cell and Molecular Medicine Rush University Medical CenterChicagoIL 60612USA

The original article was published on 19 Mar 2021,and the original article link is https://***/article/view/3789 The corresponding author declared that The Department of Defense grant support acknowledgment was incorrectly *** Department of Defense grant award that helped support this work was ***,he needed to change financial support and sponsorship in his publication in our *** to the evidence provided by the corresponding author,this work was supported by the National Cancer Institute grant(R01CA200232-05)and the Department of Defense grant(W81XWH-16-1-0025)both to maki Cg,and all of the other authors of this paper agreed with the change mentioned ***,we publish this erratum to announce this change.

关键词： journal mentioned agreed

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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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