دورية أكاديمية
Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin.
العنوان: | Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin. |
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المؤلفون: | Shields MA; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA. Electronic address: mario.shields@northwestern.edu., Spaulding C; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; Jesse Brown VA Medical Center, Chicago, IL, USA., Metropulos AE; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA., Khalafalla MG; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA., Pham TND; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA., Munshi HG; Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA. Electronic address: h-munshi@northwestern.edu. |
المصدر: | Cell reports [Cell Rep] 2022 Mar 01; Vol. 38 (9), pp. 110441. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
مواضيع طبية MeSH: | Carcinoma, Pancreatic Ductal*/drug therapy , Carcinoma, Pancreatic Ductal*/genetics , Carcinoma, Pancreatic Ductal*/metabolism , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/genetics , Pancreatic Neoplasms*/metabolism, Animals ; Cadherins/metabolism ; Carcinogenesis ; Cell Line, Tumor ; Disease Models, Animal ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; Mice ; Proto-Oncogene Proteins p21(ras)/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Pancreatic Neoplasms |
مستخلص: | Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss. Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.) |
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معلومات مُعتمدة: | R21 CA255291 United States CA NCI NIH HHS; P30 CA060553 United States CA NCI NIH HHS; I01 BX002922 United States BX BLRD VA; T32 CA070085 United States CA NCI NIH HHS; R01 CA217907 United States CA NCI NIH HHS |
فهرسة مساهمة: | Keywords: E-cadherin; Gα13; KC mouse model; KPC mouse model; human PDAC tumors; mTOR; rapamycin |
المشرفين على المادة: | 0 (Cadherins) EC 2.7.11.1 (TOR Serine-Threonine Kinases) EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, G12-G13) EC 3.6.5.2 (Hras protein, mouse) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) W36ZG6FT64 (Sirolimus) |
تواريخ الأحداث: | Date Created: 20220302 Date Completed: 20220411 Latest Revision: 20231213 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC8989626 |
DOI: | 10.1016/j.celrep.2022.110441 |
PMID: | 35235808 |
قاعدة البيانات: | MEDLINE |
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