| Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation. | |
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MedLine Citation:
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PMID: 18544666 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have defined some of the mechanisms by which the kinase inhibitor lapatinib kills HCT116 cells. Lapatinib inhibited radiation-induced activation of ERBB1/2, extracellular signal-regulated kinases 1/2, and AKT, and radiosensitized HCT116 cells. Prolonged incubation of HCT116 cells with lapatinib caused cell killing followed by outgrowth of lapatinib-adapted cells. Adapted cells were resistant to serum starvation-induced cell killing and were cross-resistant to multiple therapeutic drugs. Lapatinib was competent to inhibit basal and epidermal growth factor (EGF)-stimulated ERBB1 phosphorylation in adapted cells. Coexpression of dominant-negative ERBB1 and dominant-negative ERBB2 inhibited basal and EGF-stimulated ERBB1 and ERBB2 phosphorylation in parental and adapted cells. However, in neither parental nor adapted cells did expression of dominant-negative ERBB1 and dominant-negative ERBB2 recapitulate the cell death-promoting effects of lapatinib. Adapted cells had increased expression of MCL-1, decreased expression of BAX, and decreased activation of BAX and BAK. Overexpression of BCL-XL protected parental cells from lapatinib toxicity. Knockdown of MCL-1 expression enhanced lapatinib toxicity in adapted cells that was reverted by knockdown of BAK expression. Inhibition of caspase function modestly reduced lapatinib toxicity in parental cells, whereas knockdown of apoptosis-inducing factor expression suppressed lapatinib toxicity. Thus, in HCT116 cells, lapatinib adaptation can be mediated by altered expression of pro- and antiapoptotic proteins that maintain mitochondrial function. |
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Authors:
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Aditi Pandya Martin; Anna Miller; Luni Emad; Mohammed Rahmani; Teneille Walker; Clint Mitchell; Michael P Hagan; Margaret A Park; Adly Yacoub; Paul B Fisher; Steven Grant; Paul Dent |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2008-06-10 |
Journal Detail:
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Title: Molecular pharmacology Volume: 74 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-08-22 Completed Date: 2008-09-18 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 807-22 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298-0035, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Drug Resistance, Neoplasm
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drug effects* Drug Screening Assays, Antitumor Enzyme Activation / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism HCT116 Cells Humans Mutation / genetics* Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism* Quinazolines / pharmacology* RNA, Small Interfering / metabolism Receptor, Epidermal Growth Factor / genetics* Receptor, erbB-2 / antagonists & inhibitors Receptor, erbB-3 / metabolism Tumor Suppressor Protein p53 / genetics bcl-2 Homologous Antagonist-Killer Protein / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA104177-03/CA/NCI NIH HHS; P01 CA104177-030002/CA/NCI NIH HHS; P01-CA104177/CA/NCI NIH HHS; R01 CA088906-04/CA/NCI NIH HHS; R01 CA108520-03/CA/NCI NIH HHS; R01 DK052825-09/DK/NIDDK NIH HHS; R01-CA108520/CA/NCI NIH HHS; R01-CA63753/CA/NCI NIH HHS; R01-CA77141/CA/NCI NIH HHS; R01-DK52825/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Proto-Oncogene Proteins c-bcl-2; 0/Quinazolines; 0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/lapatinib; 0/myeloid cell leukemia sequence 1 protein; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.10.1/Receptor, erbB-3; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
| Comments/Corrections | |
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