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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

Oct-3/4 elevated the ATP binding cassette transporter G2 expression, leading to acquisition of a drug-resistant phenotype by glioblastoma cells.

GENERAL SIGNIFICANCE:

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.

• Authors: Yuki Hosokawa, Hisaaki Takahashi, Akihiro Inoue, Yuya Kawabe, Yu Funahashi, Kenji Kameda, Kana Sugimoto, Hajime Yano, Hironobu Harada, Shohei Kohno, Shiro Ohue, Takanori Ohnishi, Junya Tanaka
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1850 Issue 6 Pg. 1197-205 (Jun 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25644290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antimetabolites, Antineoplastic
• Neoplasm Proteins
• Octamer Transcription Factor-3
• POU5F1 protein, human
• Doxorubicin
• L-Lactate Dehydrogenase
• Poly(ADP-ribose) Polymerases

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Antimetabolites, Antineoplastic (metabolism, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (metabolism, pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Glioblastoma (drug therapy, genetics, metabolism, pathology)
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (metabolism)
• Octamer Transcription Factor-3 (genetics, metabolism)
• Phenotype
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection
• Tumor Burden (drug effects)