Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma
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Yoshinari Shinsato1,2, Tatsuhiko Furukawa2, Shunji Yunoue1, Hajime Yonezawa1, Kentarou Minami2,3, Yukihiko Nishizawa2,3, Ryuji Ikeda3, Kohichi Kawahara2, Masatatsu Yamamoto2, Hirofumi Hirano1, Hiroshi Tokimura1, and Kazunori Arita1
1 Department of Neurosurgery, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan;
2 Department of Molecular Oncology, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan;
3 Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences Kagoshima University, Kagoshima, Japan
Tatsuhiko Furukawa, email:
Keywords: temozolomide, MLH1, PMS2, MutL-alpha , resistance, recurrence, glioblastoma
Received: August 20, 2013 Accepted: October 12 , 2013 Published: October 14, 2013
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.
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