title: REV3L confers chemoresistance to cisplatin in human gliomas: the potential of its RNAi for synergistic therapy.
abstract: The REV3L gene, encoding the catalytic subunit of human polymerase zeta, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of certain tumors. However, the role of REV3L in regulating the sensitivity of glioma cells to chemotherapy remains unknown. In this study, we investigated the expression of the REV3L gene in 10 normal brain specimens and 30 human glioma specimens and examined the value of REV3L as a potential modulator of cellular response to various DNA-damaging agents. Reverse transcriptase PCR/real-time PCR analysis revealed that REV3L was overexpressed in human gliomas compared with normal brain tissues. A glioma cell model with stable overexpression of REV3L was used to probe the role of REV3L in cisplatin treatment; upregulation of REV3L markedly attenuated cisplatin-induced apoptosis of the mitochondrial apoptotic pathway. We therefore assessed the REV3L-targeted treatment modality that combines suppression of REV3L expression using RNA interference (RNAi) with the cytotoxic effects of DNA-damaging agents. Downregulation of REV3L expression significantly enhanced the sensitivity of glioma cells to cisplatin, as evidenced by the increased apoptosis rate and marked alterations in the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax) expression levels, and reduced mutation frequencies in surviving glioma cells. These results suggest that REV3L may potentially contribute to gliomagenesis and play a crucial role in regulating cellular response to the DNA cross-linking agent cisplatin. Our findings indicate that RNAi targeting REV3L combined with chemotherapy has synergistic therapeutic effects on glioma cells, which warrants further investigation as an effective novel therapeutic regimen for patients with this malignancy.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, First Affliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Zhang
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Weng
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Lu
authors.forename: Jingmin
authors.initials: J
authors.lastname: Yang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.forename: Caihua
authors.initials: C
authors.lastname: Xi
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Shiguang
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D015316:Genetic Therapy; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; D002945:Cisplatin