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Cited by 176Pancreatic and Hepatic Oncology ResearchProtein Kinase Regulation and GTPase SignalingCancer, Lipids, and Metabolism

The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.

Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras–Directed Therapy

Fleming, Jason B., Shen, Guo-Liang, Holloway, Shane E., Davis, Mishel, Brekken, Rolf A.·2005·Molecular Cancer Research
DOI 10.1158/1541-7786.mcr-04-0206
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Abstract

Mutation of the K-ras gene is an early event in the development of pancreatic adenocarcinoma and, therefore, RNA interference (RNAi) directed toward mutant K-ras could represent a novel therapy. In this study, we examine the phenotypic and molecular consequences of exposure of pancreatic tumor cells to mutant-specific K-ras small interfering RNA. Specific reduction of activated K-ras via RNAi in Panc-1 and MiaPaca-2 cells resulted in cellular changes consistent with a reduced capacity to form malignant tumors. These changes occur through distinct mechanisms but likely reflect an addiction of each cell line to oncogene stimulation. Both cell lines show reduced proliferation after K-ras RNAi, but only MiaPaca-2 cells showed increased apoptosis. Both cell lines showed reduced migration after K-ras knockdown, but changes in integrin levels were not consistent between the cell lines. Both cell lines showed alteration of the level of GLUT-1, a metabolism-associated gene that is downstream of c-myc, with Panc-1 cells demonstrating decreased GLUT-1 levels, whereas MiaPaca-2 cells showed increased levels of expression after K-ras knockdown. Furthermore, after K-ras RNAi, there was a reduction in angiogenic potential of both Panc-1 and MiaPaca-2 cells. Panc-1 cells increased the level of expression of thrombospondin-1, an endogenous inhibitor of angiogenesis, whereas MiaPaca-2 cells decreased the production of vascular endothelial growth factor, a primary stimulant of angiogenesis in pancreatic tumors. We have found that silencing mutant K-ras through RNAi results in alteration of tumor cell behavior in vitro and suggests that targeting mutant K-ras specifically might be effective against pancreatic cancer in vivo.

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Crossref · 10.1158/1541-7786.mcr-04-0206

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Metadata

Authors
Fleming, J. B., Shen, G.-L., Holloway, S. E., Davis, M., & Brekken, R. A.
Affiliations
  • 1Division of Surgical Oncology, Department of Surgery, and Hamon Center for Therapeutic Oncology Research and
  • The University of Texas Southwestern Medical Center (US)
ORCID
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-07-01
Volume
3
Issue
7
Pages
413-423
ISSN
  • 1541-7786 (ISSN-L)
  • 1557-3125
DOI
10.1158/1541-7786.mcr-04-0206
OpenAlex
W2154164444
Cited by
176
References
63
Citations by year
2026: 3 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 4 · 2018: 3 · 2017: 11 · 2016: 5 · 2015: 9 · 2014: 18 · 2013: 11 · 2012: 11
FWCI
5.75
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R21 CA10669)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
mutant KRAS, pancreatic ductal adenocarcinoma, RNA interference, siRNA, oncogene addiction, cell proliferation, apoptosis, cell migration, integrins, GLUT1, c-Myc, angiogenesis, thrombospondin-1, vascular endothelial growth factor, PANC-1 cells, MIA PaCa-2 cells
MeSH terms
Adenocarcinoma, Animals, Cell Movement, Humans, Immunohistochemistry, Mutation, Pancreatic Neoplasms, Genes, ras, Genetic Therapy, Gene Expression Regulation, Neoplastic, RNA, Catalytic, Apoptosis, Gene Silencing, RNA Interference, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation

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