Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases.
Alterations of the epidermal growth factor receptor (EGFR) gene occur frequently in human malignant gliomas. The most common of these is deletion of exons 2-7, resulting in truncation of the extracellular domain (DeltaEGFR or EGFRvIII), which occurs in a large fraction of de novo malignant gliomas (but not in progressive tumors or those lacking p53 function) and enhances tumorigenicity, in part by decreasing apoptosis through up-regulation of Bcl-XL. Here, we demonstrate that the DeltaEGFR concomitantly confers resistance to the chemotherapeutic drug cisplatin (CDDP) by suppression of CDDP-induced apoptosis. Expression of Bcl-XL was elevated in U87MG.DeltaEGFR cells prior to and during CDDP treatment, whereas it decreased considerably in CDDP-treated parental cells. CDDP-induced activation of caspase-3-like proteases was suppressed significantly in U87MG.DeltaEGFR cells. These responses were highly specific to constitutively kinase-active DeltaEGFR, because overexpression of kinase-deficient DeltaEGFR (DK) or wild-type EGFR had no such effects. Correspondingly, DeltaEGFR specific tyrosine kinase inhibitors reduced Bcl-XL expression and potentiated CDDP-induced apoptosis in U87MG.DeltaEGFR cells. Ectopic overexpression of Bcl-XL in parental U87MG cells also resulted in suppression of both caspase activation and apoptosis induced by CDDP. These results may have important clinical implications for the use of CDDP in the treatment of those malignant gliomas expressing DeltaEGFR.
Nagane
M
M
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0660, USA.
Levitzki
A
A
Gazit
A
A
Cavenee
W K
WK
Huang
H J
HJ
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin / Q000627:therapeutic use; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics*; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020032:Tyrphostins; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D020032:Tyrphostins; D051020:bcl-X Protein; C101044:RTKI cpd; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D002945:Cisplatin