Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance - PubMed (original) (raw)
. 2008 Nov;22(11):2080-90.
doi: 10.1038/leu.2008.207. Epub 2008 Aug 7.
S L Abrams, G Ligresti, N Misaghian, E W T Wong, L S Steelman, J Bäsecke, J Troppmair, M Libra, F Nicoletti, S Molton, M McMahon, C Evangelisti, A M Martelli
Affiliations
- PMID: 18685611
- DOI: 10.1038/leu.2008.207
Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance
J A McCubrey et al. Leukemia. 2008 Nov.
Abstract
A cytokine-dependent (FL5.12), drug-sensitive, p53 wild type (WT) and a doxorubicin-resistant derivative line (FL/Doxo) were used to determine the mechanisms that could result in drug resistance of early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was due to a higher level of proteasomal degradation of p53. Dominant-negative (DN) p53 genes increased the resistance to chemotherapeutic drugs, MDM-2 and MEK inhibitors, further substantiating the role of p53 in therapeutic sensitivity. The involvement of signal transduction and apoptotic pathways was examined, as drug resistance did not appear to be due to increased drug efflux. Drug-resistant FL/Doxo cells had higher levels of activated Raf/MEK/ERK signaling and decreased induction of apoptosis when cultured in the presence of doxorubicin than drug-sensitive FL5.12 cells. Introduction of DN MEK1 increased drug sensitivity, whereas constitutively active (CA) MEK1 or conditionally active BRAF augmented resistance, documenting the importance of the Raf/MEK/ERK pathway in drug resistance. MEK inhibitors synergized with chemotherapeutic drugs to reduce the IC(50). Thus the p53 and Raf/MEK/ERK pathways play key roles in drug sensitivity. Targeting these pathways may be effective in certain drug-resistant leukemias that are WT at p53.
Similar articles
- Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance.
McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M. McCubrey JA, et al. Adv Enzyme Regul. 2006;46:249-79. doi: 10.1016/j.advenzreg.2006.01.004. Epub 2006 Jul 18. Adv Enzyme Regul. 2006. PMID: 16854453 - Resistance to mitogen-activated protein kinase kinase (MEK) inhibitors correlates with up-regulation of the MEK/extracellular signal-regulated kinase pathway in hepatocellular carcinoma cells.
Yip-Schneider MT, Klein PJ, Wentz SC, Zeni A, Menze A, Schmidt CM. Yip-Schneider MT, et al. J Pharmacol Exp Ther. 2009 Jun;329(3):1063-70. doi: 10.1124/jpet.108.147306. Epub 2009 Mar 3. J Pharmacol Exp Ther. 2009. PMID: 19258520 - The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy.
Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Bäsecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA. Abrams SL, et al. Cell Cycle. 2010 May;9(9):1781-91. doi: 10.4161/cc.9.9.11483. Epub 2010 May 10. Cell Cycle. 2010. PMID: 20436278 Free PMC article. - Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA. McCubrey JA, et al. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7. Biochim Biophys Acta. 2007. PMID: 17126425 Free PMC article. Review. - Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy.
Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA. Steelman LS, et al. Leukemia. 2011 Jul;25(7):1080-94. doi: 10.1038/leu.2011.66. Epub 2011 Apr 15. Leukemia. 2011. PMID: 21494257 Review.
Cited by
- Occupational exposure to carcinogens: Benzene, pesticides and fibers (Review).
Falzone L, Marconi A, Loreto C, Franco S, Spandidos DA, Libra M. Falzone L, et al. Mol Med Rep. 2016 Nov;14(5):4467-4474. doi: 10.3892/mmr.2016.5791. Epub 2016 Oct 3. Mol Med Rep. 2016. PMID: 27748850 Free PMC article. Review. - Targeting signal transduction pathways to eliminate chemotherapeutic drug resistance and cancer stem cells.
McCubrey JA, Abrams SL, Stadelman K, Chappell WH, Lahair M, Ferland RA, Steelman LS. McCubrey JA, et al. Adv Enzyme Regul. 2010;50(1):285-307. doi: 10.1016/j.advenzreg.2009.10.016. Epub 2009 Nov 4. Adv Enzyme Regul. 2010. PMID: 19895837 Free PMC article. Review. No abstract available. - Fluoro-edenite induces fibulin-3 overexpression in non-malignant human mesothelial cells.
Rapisarda V, Salemi R, Marconi A, Loreto C, Graziano AC, Cardile V, Basile MS, Candido S, Falzone L, Spandidos DA, Fenga C, Libra M. Rapisarda V, et al. Oncol Lett. 2016 Nov;12(5):3363-3367. doi: 10.3892/ol.2016.5051. Epub 2016 Aug 26. Oncol Lett. 2016. PMID: 27900005 Free PMC article. - miR-202 Suppresses Cell Proliferation by Targeting FOXR2 in Endometrial Adenocarcinoma.
Deng X, Hou C, Liang Z, Wang H, Zhu L, Xu H. Deng X, et al. Dis Markers. 2017;2017:2827435. doi: 10.1155/2017/2827435. Epub 2017 Jul 30. Dis Markers. 2017. PMID: 28827892 Free PMC article. - Bile duct ligation elevates 5-HT levels in cerebral cortex of rats partly due to impairment of brain UGT1A6 expression and activity via ammonia accumulation.
Yang H, You L, Wang Z, Yang L, Wang X, Wu W, Zhi H, Rong G, Sheng Y, Liu X, Liu L. Yang H, et al. Redox Biol. 2024 Feb;69:103019. doi: 10.1016/j.redox.2023.103019. Epub 2023 Dec 28. Redox Biol. 2024. PMID: 38163420 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous