Oct-3/4 modulates the drug-resistant phenotype of glioblastoma cells through expression of ATP binding cassette transporter G2

• Published in: Biochimica et biophysica acta Vol. 1850; no. 6; pp. 1197 - 1205
• Main Authors: Hosokawa, Yuki, Takahashi, Hisaaki, Inoue, Akihiro, Kawabe, Yuya, Funahashi, Yu, Kameda, Kenji, Sugimoto, Kana, Yano, Hajime, Harada, Hironobu, Kohno, Shohei, Ohue, Shiro, Ohnishi, Takanori, Tanaka, Junya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2015
• Subjects: ABC transporter; ABC transporters; Animals; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacology; antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Dose-Response Relationship, Drug; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - genetics; drug therapy; excretion; genes; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; L-Lactate Dehydrogenase - metabolism; lactate dehydrogenase; Male; Mice, Inbred BALB C; Mice, Nude; NAD ADP-ribosyltransferase; Neoplasm Proteins - metabolism; neoplasms; Oct-3/4; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; patients; Phenotype; Poly(ADP-ribose) Polymerases - metabolism; prognosis; quantitative polymerase chain reaction; RNA Interference; Signal Transduction; stem cells; Time Factors; Transfection; Tumor Burden - drug effects; PBS; ABC; HIF; Glioblastoma; PARP; EGFP; Doxy; Drug resistance; DMEM; LDH; PI3K; FBS; Oct-3/4; qPCR; MDR; GB; AID; HE; ABC transporter
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2015.01.017

Drug resistance is a major obstacle for the efficacy of chemotherapeutic treatment of tumors. Oct-3/4, a self-renewal regulator in stem cells, is expressed in various kinds of solid tumors including glioblastoma. Although Oct-3/4 expression has been implicated in the malignancy and prognosis of glioblastomas, little is known of its involvement in drug resistances of glioblastoma. The involvement of Oct-3/4 in drug resistance of glioblastoma cells was assessed by lactate dehydrogenase assay, efflux assay of an anticancer drug, poly ADP-ribose polymerase cleavage, and in vivo xenograft experiments. Involvement of a drug efflux pump ATP binding cassette transporter G2 in Oct-3/4-induced drug resistance was evaluated by quantitative PCR analysis and knockdown by shRNA. Oct-3/4 decreased the susceptibility to chemotherapeutic drugs by enhancing excretion of drugs through a drug efflux pump gene, ATP binding cassette transporter G2. Moreover, the expression of Oct-3/4 was well correlated to ATP binding cassette transporter G2 expression in clinical GB tissues. Oct-3/4 elevated the ATP binding cassette transporter G2 expression, leading to acquisition of a drug-resistant phenotype by glioblastoma cells. If the drug-resistance of glioblastoma cells could be suppressed, it should be a highly ameliorative treatment for glioblastoma patients. Therefore, signaling pathways from Oct-3/4 to ATP binding cassette transporter G2 should be intensively elucidated to develop new therapeutic interventions for better efficacy of anti-cancer drugs. •Oct-3/4 decreases the susceptibility to chemotherapeutic drugs on glioblastoma cells.•Oct-3/4 strengthens the drug-resistance of glioblastoma cells by elevating expression of a drug efflux pump gene, ABCG2.•Expression of Oct-3/4 is well correlated to ABCG2 expression in clinical glioblastoma tissues.