دورية أكاديمية
Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway.
| العنوان: | Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway. |
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| المؤلفون: | Ludwig MP; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Galbraith MD; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Eduthan NP; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Hill AA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Clay MR; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Tellez CM; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Wilky BA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Elias A; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Espinosa JM; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado., Sullivan KD; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado.; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. |
| المصدر: | Cancer research [Cancer Res] 2023 Aug 01; Vol. 83 (15), pp. 2543-2556. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Liposarcoma*/drug therapy , Liposarcoma*/genetics , Antineoplastic Agents*/pharmacology, Humans ; Proteasome Endopeptidase Complex/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/genetics ; Proteasome Inhibitors/pharmacology ; Apoptosis ; Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism |
| مستخلص: | Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacologic studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma. Significance: Targeting the proteasome in combination with MDM2 inhibition activates the ATF4/CHOP stress response axis to induce apoptosis in liposarcoma, providing a potential therapeutic approach for the most common soft-tissue sarcoma. (©2023 The Authors; Published by the American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P30 CA046934 United States CA NCI NIH HHS; R01 CA117907 United States CA NCI NIH HHS |
| المشرفين على المادة: | EC 3.4.25.1 (Proteasome Endopeptidase Complex) 53IA0V845C (nutlin 3) EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) 0 (Tumor Suppressor Protein p53) 0 (Antineoplastic Agents) 0 (Proteasome Inhibitors) EC 2.3.2.27 (MDM2 protein, human) 0 (PSMD9 protein, human) 0 (ATF4 protein, human) 145891-90-3 (Activating Transcription Factor 4) |
| تواريخ الأحداث: | Date Created: 20230519 Date Completed: 20230803 Latest Revision: 20240716 |
| رمز التحديث: | 20240716 |
| مُعرف محوري في PubMed: | PMC10391328 |
| DOI: | 10.1158/0008-5472.CAN-22-3173 |
| PMID: | 37205634 |
| قاعدة البيانات: | MEDLINE |
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