Document Detail

Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation.
MedLine Citation:
PMID:  18544666     Owner:  NLM     Status:  MEDLINE    
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.
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:
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:
Title:  Molecular pharmacology     Volume:  74     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-22     Completed Date:  2008-09-18     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  807-22     Citation Subset:  IM    
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MeSH Terms
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism
HCT116 Cells
Mutation / genetics*
Myeloid Cell Leukemia Sequence 1 Protein
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
P01 CA104177/CA/NCI NIH HHS; P01 CA104177-03/CA/NCI NIH HHS; P01 CA104177-030002/CA/NCI NIH HHS; P01-CA104177/CA/NCI NIH HHS; R01 CA088906/CA/NCI NIH HHS; R01 CA088906-04/CA/NCI NIH HHS; R01 CA108520/CA/NCI NIH HHS; R01 CA108520-03/CA/NCI NIH HHS; R01 CA150214/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK 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
Reg. No./Substance:
0/Myeloid Cell Leukemia Sequence 1 Protein; 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; 0VUA21238F/lapatinib; EC protein, human; EC, Epidermal Growth Factor; EC, erbB-2; EC, erbB-3; EC Proteins c-akt; EC Signal-Regulated MAP Kinases

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