SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-08-2640. This Article Full Text (PDF) All Versions of this Article: 2002-08-2640v1 101/8/3126    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hu, L. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Hu, L. Articles by Lichtenstein, A. Social Bookmarking                   What's this? Submitted August 29, 2002 Accepted November 22, 2002 Downstream effectors of oncogenic ras in multiple myeloma cells Liping Hu, Yijiang Shi, Jung-hsin Hsu, Joseph Gera, Brian Van Ness, and Alan Lichtenstein* Department of Hematology-Oncology, VA West LA-UCLA Medical Center, Los Angeles, CA, USA Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA * Corresponding author; email: alichten{at}ucla.edu. Ectopic expression of mutated K-ras or N-ras in the IL-6-dependent ANBL6 multiple myeloma cell line induces cytokine-independent growth. To investigate the signaling pathways activated by oncogenic ras that may stimulate IL-6-independent growth, we compared ANBL6 cells stably transfected with mutated K or N-ras genes to wild type ras-expressing control cells identically transfected with an empty vector. Upon depletion of IL-6, both mutated ras-containing myeloma lines demonstrated constitutive activation of MEK/ERK, PI3-kinase/AKT, mTOR/p70S6 kinase, and NF-kB pathways. In contrast, STAT3 was not constitutively tyrosine phosphorylated in mutant ras-expressing cells. We used several maneuvers in attempts to selectively target these constitutively active pathways. The mTOR inhibitors rapamycin and CCI-779, the PI3-kinase inhibitor Ly294002, and the MEK inhibitor PD 98059 all significantly curtailed growth of mutant ras-containing cells. Farnesyl transferase inhibitors, used to target ras itself, had modest effects only against mutant N-ras-containing cells. Growth of mutant N-ras containing myeloma cells was also inhibited by acute expression of the IKB super repressor gene which abrogated NF-kB activation. These results indicate several pathways are activated downstream of oncogenic ras in myeloma cells which contribute to stimulation of cytokine-independent growth. They also suggest that therapeutic strategies which target these pathways may be particularly efficacious in patients whose myeloma clones contain ras mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Shi, P. J. Frost, B. Q. Hoang, A. Benavides, S. Sharma, J. F. Gera, and A. K. Lichtenstein IL-6-Induced Stimulation of c-Myc Translation in Multiple Myeloma Cells Is Mediated by Myc Internal Ribosome Entry Site Function and the RNA-Binding Protein, hnRNP A1 Cancer Res., December 15, 2008; 68(24): 10215 - 10222. [Abstract] [Full Text] [PDF] Y.-T. Tai, M. Fulciniti, T. Hideshima, W. Song, M. Leiba, X.-F. Li, M. Rumizen, P. Burger, A. Morrison, K. Podar, et al. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis Blood, September 1, 2007; 110(5): 1656 - 1663. [Abstract] [Full Text] [PDF] Y. Shi, T. Reiman, W. Li, C. A. Maxwell, S. Sen, L. Pilarski, T. R. Daniels, M. L. Penichet, R. Feldman, and A. Lichtenstein Targeting aurora kinases as therapy in multiple myeloma Blood, May 1, 2007; 109(9): 3915 - 3921. [Abstract] [Full Text] [PDF] P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF] H.-S. Shiah, W. Gao, D. C. Baker, and Y.-C. Cheng Inhibition of cell growth and nuclear factor-{kappa}B activity in pancreatic cancer cell lines by a tylophorine analogue, DCB-3503. Mol. Cancer Ther., October 1, 2006; 5(10): 2484 - 2493. [Abstract] [Full Text] [PDF] V. Dasari, M. Gallup, H. Lemjabbar, I. Maltseva, and N. McNamara Epithelial-Mesenchymal Transition in Lung Cancer: Is Tobacco the "Smoking Gun"? Am. J. Respir. Cell Mol. Biol., July 1, 2006; 35(1): 3 - 9. [Full Text] [PDF] B. Hoang, L. Zhu, Y. Shi, P. Frost, H. Yan, S. Sharma, S. Sharma, L. Goodglick, S. Dubinett, and A. Lichtenstein Oncogenic RAS mutations in myeloma cells selectively induce cox-2 expression, which participates in enhanced adhesion to fibronectin and chemoresistance Blood, June 1, 2006; 107(11): 4484 - 4490. [Abstract] [Full Text] [PDF] H. Yan, P. Frost, Y. Shi, B. Hoang, S. Sharma, M. Fisher, J. Gera, and A. Lichtenstein Mechanism by Which Mammalian Target of Rapamycin Inhibitors Sensitize Multiple Myeloma Cells to Dexamethasone-Induced Apoptosis Cancer Res., February 15, 2006; 66(4): 2305 - 2313. [Abstract] [Full Text] [PDF] E. David, S.-Y. Sun, E. K. Waller, J. Chen, F. R. Khuri, and S. Lonial The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT Blood, December 15, 2005; 106(13): 4322 - 4329. [Abstract] [Full Text] [PDF] Y. Shi, H. Yan, P. Frost, J. Gera, and A. Lichtenstein Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade Mol. Cancer Ther., October 1, 2005; 4(10): 1533 - 1540. [Abstract] [Full Text] [PDF] M. Ladetto, S. Vallet, A. Trojan, M. Dell'Aquila, L. Monitillo, R. Rosato, L. Santo, D. Drandi, A. Bertola, P. Falco, et al. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome Blood, June 15, 2005; 105(12): 4784 - 4791. [Abstract] [Full Text] [PDF] M. Gomez-Benito, I. Marzo, A. Anel, and J. Naval Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination Mol. Pharmacol., June 1, 2005; 67(6): 1991 - 1998. [Abstract] [Full Text] [PDF] C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF] N. W.C.J. van de Donk, H. M. Lokhorst, E. H.J. Nijhuis, M. M.J. Kamphuis, and A. C. Bloem Geranylgeranylated Proteins are Involved in the Regulation of Myeloma Cell Growth Clin. Cancer Res., January 15, 2005; 11(2): 429 - 439. [Abstract] [Full Text] [PDF] H. Jernberg-Wiklund and K. Nilsson Toward a rational combinaTORial therapy for multiple myeloma Blood, December 15, 2004; 104(13): 3845 - 3846. [Full Text] [PDF] P. Frost, F. Moatamed, B. Hoang, Y. Shi, J. Gera, H. Yan, P. Frost, J. Gibbons, and A. Lichtenstein In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model Blood, December 15, 2004; 104(13): 4181 - 4187. [Abstract] [Full Text] [PDF] N. Raje, S. Kumar, T. Hideshima, K. Ishitsuka, D. Chauhan, C. Mitsiades, K. Podar, S. Le Gouill, P. Richardson, N. C. Munshi, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma Blood, December 15, 2004; 104(13): 4188 - 4193. [Abstract] [Full Text] [PDF] T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF] T. Stromberg, A. Dimberg, A. Hammarberg, K. Carlson, A. Osterborg, K. Nilsson, and H. Jernberg-Wiklund Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone Blood, April 15, 2004; 103(8): 3138 - 3147. [Abstract] [Full Text] [PDF] B. Barlogie, J. Shaughnessy, G. Tricot, J. Jacobson, M. Zangari, E. Anaissie, R. Walker, and J. Crowley Treatment of multiple myeloma Blood, January 1, 2004; 103(1): 20 - 32. [Abstract] [Full Text] [PDF] J. Zhang, M. Socolovsky, A. W. Gross, and H. F. Lodish Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system Blood, December 1, 2003; 102(12): 3938 - 3946. [Abstract] [Full Text] [PDF] N. Ochiai, R. Uchida, S.-i. Fuchida, A. Okano, M. Okamoto, E. Ashihara, T. Inaba, N. Fujita, H. Matsubara, and C. Shimazaki Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro Blood, November 1, 2003; 102(9): 3349 - 3353. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020