Oct-3/4 modulates the drug-resistant phenotype of glioblastoma cells through expression of ATP binding cassette transporter G2
Oct-3/4 modulates the drug-resistant phenotype of glioblastoma cells through expression of ATP binding cassette transporter G2
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DOI：
10.1016/j.bbagen.2015.01.017
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发表时间：
2015-06-01
影响因子：
3
通讯作者：
Tanaka, Junya
中科院分区：
文献类型：
--
作者：
Hosokawa, Yuki;Takahashi, Hisaaki;Tanaka, Junya
背景：耐药是影响肿瘤化疗效果的主要障碍。Oct-3/4是干细胞自我更新调节因子，在包括胶质母细胞瘤在内的多种实体肿瘤中表达。尽管Oct-3/4表达与胶质母细胞瘤的恶性和预后有关，但其与胶质母细胞瘤耐药的关系尚不清楚。方法：通过乳酸脱氢酶实验、抗癌药物外排实验、聚adp核糖聚合酶裂解实验和体内异种移植实验，评估Oct-3/4在胶质母细胞瘤细胞耐药中的作用。采用定量PCR和shRNA敲低的方法评价药物外排泵ATP结合盒转运体G2在oct -3/4诱导的耐药过程中的作用。结果：Oct-3/4通过药物外排泵基因ATP结合盒转运体G2促进药物排泄，从而降低化疗药物敏感性。此外，Oct-3/4的表达与临床GB组织中ATP结合盒转运体G2的表达有良好的相关性。结论：Oct-3/4上调ATP结合盒转运体G2的表达，导致胶质母细胞瘤细胞获得耐药表型。一般意义：如果能抑制胶质母细胞瘤细胞的耐药，对胶质母细胞瘤患者应是一种具有高度改善作用的治疗方法。因此，需要深入研究Oct-3/4到ATP结合盒转运体G2的信号通路，以开发新的治疗干预措施，提高抗癌药物的疗效。(C) 2015 Elsevier B.V.版权所有
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. (C) 2015 Elsevier B.V. All rights reserved.