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Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras–Directed Therapy
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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“Silencing mutant KRAS in human pancreatic cancer cells using specific siRNA effectively reduces KRAS expression, leading to a dose-dependent decrease in KRAS protein levels.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [125]
In the citing paper
“In KRAS mutant pancreatic cancer cells, acute silencing of KRAS via RNAi or CRISPR results in cell cycle arrest, apoptosis and suppression of anchorage-independent proliferation in vitro, and attenuated tumor growth and metastasis in xenograft models (66–68).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [66]
Citations
Cites
2 retracted
Watnick, R. S., Cheng, Y.-N., Rangarajan, A., Ince, T. A., & Weinberg, R. A. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00030-8 · Cited by 318
RetractedIto, H., Duxbury, M. S., Zinner, M. J., Ashley, S. W., & Whang, E. E. (2004) · Surgery · doi:10.1016/j.surg.2004.05.032 · Cited by 86
RetractedHanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425
Spencer, P. M., Cameron, J. L., & Lin, L. (2000) · Cited by 7,202
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559
On Respiratory Impairment in Cancer Cells
Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472
Targeting RAS signalling pathways in cancer therapy
Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,354
Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes
Land, H., Parada, L. F., & Weinberg, R. A. (1983) · Nature · doi:10.1038/304596a0 · Cited by 2,804
Addiction to Oncogenes--the Achilles Heal of Cancer
Weinstein, I. B. (2002) · Science · doi:10.1126/science.1073096 · Cited by 1,764
Li, D., Xie, K., Wolff, R. A., & Abbruzzese, J. L. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15841-8 · Cited by 1,731
Multiple Ras-dependent phosphorylation pathways regulate Myc protein stabilityPreprint
Sears, R. C., Nuckolls, F., Haura, E. B., Taya, Y., Tamai, K., & Nevins, J. R. (2000) · Genes & Development · doi:10.1101/gad.836800 · Cited by 1,411
Activation of the interferon system by short-interfering RNAs
Sledz, C. A., Holko, M., de Veer, M. J., Silverman, R. H., & Williams, B. R. G. (2003) · Nature Cell Biology · doi:10.1038/ncb1038 · Cited by 1,401
Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB
Kauffmann-Zeh, A., Rodriguez‐Viciana, P., Ulrich, E., Gilbert, C. S., Coffer, P. J., Downward, J., & Evan, G. I. (1997) · Nature · doi:10.1038/385544a0 · Cited by 1,144
Jemal, A., Clegg, L. X., Ward, E., Ries, L. A. G., Wu, X., Jamison, P. M., Wingo, P. A., Howe, H. L., Anderson, R. N., & Edwards, B. K. (2004) · Cancer · doi:10.1002/cncr.20288 · Cited by 1,141
Reversible Tumorigenesis by MYC in Hematopoietic Lineages
Felsher, D. W., & Bishop, J. M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80367-6 · Cited by 895
Stable suppression of tumorigenicity by virus-mediated RNA interference
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00122-8 · Cited by 886
Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc
Osthus, R. C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., Xu, Y., Wonsey, D. R., Lee, L. A., & Dang, C. V. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000023200 · Cited by 876
Yeh, E., Cunningham, M., Arnold, H., Chasse, D., Monteith, T., Ivaldi, G., Hahn, W. C., Stukenberg, P. T., Shenolikar, S., Uchida, T., et al. (2004) · Nature Cell Biology · doi:10.1038/ncb1110 · Cited by 791
Sinn, E., Muller, W. J., Pattengale, P. K., Tepler, I., Wallace, R., & Leder, P. (1987) · Cell · doi:10.1016/0092-8674(87)90449-1 · Cited by 788
Flier, J. S., Mueckler, M., Usher, P., & Lodish, H. F. (1987) · Science · doi:10.1126/science.3103217 · Cited by 783
Tumor-suppressive pathways in pancreatic carcinoma.
Rozenblum, E., Schutte, M. E. M., Goggins, M., Hahn, S. A., Panzer, S., ZAHURAK, M. L., Goodman, S. N., Sohn, T. A., Hruban, R. H., Yeo, C. J., et al. (1997) · PubMed · Cited by 693
Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC
Jain, M., Arvanitis, C., Chu, K., Dewey, W. C., Leonhardt, E. A., Trinh, M., Sundberg, C. D., Bishop, J. M., & Felsher, D. W. (2002) · Science · doi:10.1126/science.1071489 · Cited by 661
Short interfering RNA confers intracellular antiviral immunity in human cells
Gitlin, L., Karelsky, S., & Andino, R. (2002) · Nature · doi:10.1038/nature00873 · Cited by 605
Reversible Activation of c-Myc in Skin
Pelengaris, S., Littlewood, T. D., Khan, M., Elia, G., & Evan, G. I. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80350-0 · Cited by 469
Over-expression of facilitative glucose transporter genes in human cancer
Yamamoto, T., Seino, Y., Fukumoto, H., Koh, G., Yano, H., Inagaki, N., Yamada, Y., Inoue, K., Manabe, T., & Imura, H. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(90)91263-r · Cited by 465
Demographic variations in the rising incidence of esophageal adenocarcinoma in white males
Bollschweiler, E., Wolfgarten, E., Gutschow, C. A., & H�lscher, A. H. (2001) · Cancer · doi:10.1002/1097-0142(20010801)92:3 · Cited by 452
Transient excess of MYC activity can elicit genomic instability and tumorigenesis
Felsher, D. W., & Bishop, J. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3940 · Cited by 427
Leder, A., Pattengale, P. K., Kuo, A., Stewart, T. A., & Leder, P. (1986) · Cell · doi:10.1016/0092-8674(86)90280-1 · Cited by 419
D’Cruz, C. M., Gunther, E. J., Boxer, R. B., Hartman, J. L., Sintasath, L., Moody, S. E., Cox, J. D., Ha, S. I., Belka, G. K., Golant, A., et al. (2001) · Nature Medicine · doi:10.1038/84691 · Cited by 418
Schmidt, C. M. (2004) · Archives of Surgery · doi:10.1001/archsurg.139.7.718 · Cited by 390
Telford, W. G., King, L. E., & Fraker, P. J. (1992) · Cytometry · doi:10.1002/cyto.990130205 · Cited by 367
Ki-ras oncogene activation in preinvasive pancreatic cancer
Lemoine, N. R., Jain, S., Hughes, C. M., Staddon, S. L., Maillet, B., Hall, P. A., & Klöppel, G. (1992) · Gastroenterology · doi:10.1016/0016-5085(92)91805-e · Cited by 247
A Large Scale Genetic Analysis of c-Myc-regulated Gene Expression Patterns
O’Connell, B. C., Cheung, A. F., Simkevich, C. P., Tam, W., Ren, X., Mateyak, M. K., & Sedivy, J. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210462200 · Cited by 227
Frederick, J. P., Liberati, N. T., Waddell, D. S., Shi, Y., & Wang, X. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.6.2546-2559.2004 · Cited by 221
Zhu, S., Yoon, K., Sterneck, E., Johnson, P. F., & Smart, R. C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012437299 · Cited by 199
Connecting proliferation and apoptosis in development and disease
Hipfner, D. R., & Cohen, S. M. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1491 · Cited by 193
Quantitative proteomic analysis of Myc oncoprotein function
Shiio, Y., Donohoe, S., Yi, E. C., Goodlett, D. R., Aebersold, R. H., & Eisenman, R. N. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf525 · Cited by 183
Zhu, S., Oh, H.-S., Shim, M., Sterneck, E., Johnson, P. F., & Smart, R. C. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.10.7181 · Cited by 151
Chapter 15 Simultaneous Measurement of Cell Cycle and Apoptotic Cell Death
Moore, A., Donahue, C. J., Bauer, K. D., & Mather, J. P. (1998) · Methods in cell biology · doi:10.1016/s0091-679x(08)61584-8 · Cited by 138
Integrin α5β1 Promotes Survival of Growth-Arrested Breast Cancer Cells
Korah, R. M., Boots, M., & Wieder, R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3853 · Cited by 131
Knies, U. E., Fox, S. B., Poulsom, R., Evan, G. I., & Harris, A. L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3176 · Cited by 121
Role of Angiogenesis in the Development and Growth of Liver Metastasis
Takeda, A., Stoeltzing, O., Ahmad, S. A., Reinmuth, N., Liu, W., Parikh, A. A., Fan, F., Akagi, M., & Ellis, L. M. (2002) · Annals of Surgical Oncology · doi:10.1007/bf02574475 · Cited by 112
Biology of angiogenesis in tumors of the gastrointestinal tract
Reinmuth, N., Parikh, A. A., Ahmad, S. A., Liu, W., Stoeltzing, O., Fan, F., Takeda, A., Akagi, M., & Ellis, L. M. (2003) · Microscopy Research and Technique · doi:10.1002/jemt.10258 · Cited by 103
Farnesyltransferase inhibitors
Sebti, S. M., & Adjei, A. A. (2004) · Seminars in Oncology · doi:10.1053/j.seminoncol.2003.12.012 · Cited by 100
Kita, K., Saito, S., Morioka, C. Y., & Watanabe, A. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990209)80:4 · Cited by 82
Oncogenes and tumor angiogenesis
Rak, J. W., & Yu, J. (2004) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2003.09.014 · Cited by 76
CEACAM6 is a determinant of pancreatic adenocarcinoma cellular invasiveness
Duxbury, M. S., Ito, H., Benoit, E., Ashley, S. W., & Whang, E. E. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602113 · Cited by 75
Molecular therapy in pancreatic adenocarcinoma
MacKenzie, M. J. (2004) · The Lancet Oncology · doi:10.1016/s1470-2045(04)01565-7 · Cited by 73
Mouse models of pancreatic cancer
Leach, S. D. (2004) · Cancer Cell · doi:10.1016/s1535-6108(03)00337-4 · Cited by 72
Feinberg, M. W., Watanabe, M., Lebedeva, M. A., DePina, A., Hanai, J.-I., Mammoto, T., Frederick, J. P., Wang, X.-F., Sukhatme, V. P., & Jain, M. K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309664200 · Cited by 65
Yan, Z., Chen, M.-X., Perucho, M., & Friedman, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.49.30928 · Cited by 57
Yan, Z., Deng, X., Chen, M., Xu, Y., Ahram, M. A., Sloane, B. F., & Friedman, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.27902 · Cited by 49
Development of gene therapy to target pancreatic cancer
Yoshida, T., Ohnami, S., & Aoki, K. (2004) · Cancer Science · doi:10.1111/j.1349-7006.2004.tb03204.x · Cited by 44
van Golen, C. M., Soules, M. E., Grauman, A., & Feldman, E. L. (2003) · Oncogene · doi:10.1038/sj.onc.1206362 · Cited by 43
Corbí, A. L., Jensen, U. B., & Watt, F. M. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01591-x · Cited by 39
The Effect of Thrombospondin-1 and TGF-β1 on Pancreatic Cancer Cell Invasion
Albo, D., Berger, D. H., & Tuszynski, G. P. (1998) · Journal of Surgical Research · doi:10.1006/jsre.1998.5299 · Cited by 38
Cancer Cell Biology: Myc Wins the Competition
Donaldson, T. D., & Duronio, R. J. (2004) · Current Biology · doi:10.1016/j.cub.2004.05.035 · Cited by 27
Molecular-Targeted Agents in Pancreatic Cancer
Saad, E. D., & Hoff, P. M. (2004) · Cancer Control · doi:10.1177/107327480401100105 · Cited by 27
β1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts
Brakebusch, C., Wennerberg, K., Krell, H. W., Weidle, U. H., Sallmyr, A., Johansson, S., & Fässler, R. (1999) · Oncogene · doi:10.1038/sj.onc.1202770 · Cited by 26
Detection of low-fraction K-ras mutations in primary lung tumors using a sensitive method
Keohavong, P., Zhu, D., Melacrinos, A. C., Demichele, M., Weyant, R. J., Luketich, J. D., Testa, J. R., Feder, M., & Siegfried, J. M. (1997) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19970422)74:2 · Cited by 18
Oligonucleotide Treatment of RAS-Induced Tumors in Nude Mice
Wickstrom, E. (2001) · Molecular Biotechnology · doi:10.1385/mb:18:1:35 · Cited by 16
Suppression of Pancreatic and Colon Cancer Cells by Antisense K-ras RNA Expression Vectors
Aoki, K., Ohnami, S., & Yoshida, T. (2004) · Humana Press eBooks · doi:10.1385/1-59259-854-4:193 · Cited by 11
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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)
- Venue
- Molecular Cancer Research
- Published
- 2005-07-01
- Volume
- 3
- Issue
- 7
- Pages
- 413-423
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- 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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