title: Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma.
abstract: Although there is a relationship between DNA repair deficiency and temozolomide (TMZ) resistance in glioblastoma (GBM), it remains unclear which molecule is associated with GBM recurrence. We isolated three TMZ-resistant human GBM cell lines and examined the expression of O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) components. We used immunohistochemical analysis to compare MutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2) and MGMT expression in primary and recurrent GBM specimens obtained from GBM patients during TMZ treatment. We found a reduction in MLH1 expression and a subsequent reduction in PMS2 protein levels in TMZ-resistant cells. Furthermore, MLH1 or PMS2 knockdown confered TMZ resistance. In recurrent GBM tumours, the expression of MLH1 and PMS2 was reduced when compared to primary tumours.
authors.affiliation: Department of Neurosurgery, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Shinsato
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.forename: Shunji
authors.initials: S
authors.lastname: Yunoue
authors.forename: Hajime
authors.initials: H
authors.lastname: Yonezawa
authors.forename: Kentarou
authors.initials: K
authors.lastname: Minami
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hirano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tokimura
authors.forename: Kazunori
authors.initials: K
authors.lastname: Arita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D000077204:Temozolomide; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes; D000077204:Temozolomide