Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression.
Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitrosourea) is the most commonly used chemotherapeutic agent for gliomas. However, the usefulness of this agent is limited because tumor cell resistance to BCNU is frequently found in clinical brain tumor therapy. The O6-methylguanine-DNA methyltransferase protein (MGMT) reverses alkylation at the O6 position of guanine and we have reported the role of MGMT in the response of brain tumors to alkylating agents. However, the different mechanisms underlying the patterns related to MGMT remain unclear. To better understand the molecular mechanism by which BCNU exerts its effect in glioma cell lines according MGMT expression, we used microarray technology to interrogate 3800 known genes and determine the gene expression profiles altered by BCNU treatment. Our results showed that treatment with BCNU alters the expression of a diverse group of genes in a time-dependent manner. A subset of gene changes was found common in both glioma cell lines and other subset is specific of each cell line. After 24 h of BCNU treatment, up-regulation of transcription factors involved in the nucleation of both RNA polymerase II and III transcription initiation complexes was reported. Interestingly, BCNU promoted the expression of actin-dependent regulators of chromatin. Similar effects were found with higher BCNU doses in MGMT+ cell line showing a similar mechanism that in MGMT-deficient cell with standard doses. Our data suggest that human glioma cell lines treated with BCNU, independently of MGMT expression, show changes in the expression of cell cycle and survival-related genes interfering the transcription mechanisms and the chromatin regulation.
Laboratory of Biotechnology and Pharmacogenomics, University Clinic, Cancer Center, University of Navarra, Avda Pio XII 36, 31008, Pamplona, Spain. ebandres@unav.es
Eva
E
Bandres
Esther
E
Andion
Alvaro
A
Escalada
Beatriz
B
Honorato
Victoria
V
Catalan
Elena
E
Cubedo
Lucia
L
Cordeu
Fermin
F
Garcia
Ruth
R
Zarate
Natalia
N
Zabalegui
Jesus
J
Garcia-Foncillas
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics*; D002330:Carmustine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics*; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis* / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation
D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine