Bone morphogenetic protein 7 sensitizes O6-methylguanine methyltransferase expressing-glioblastoma stem cells to clinically relevant dose of temozolomide

Molecular Cancer

Research

Stanley F. Nelson¹  Timothy F. Cloughesy²  Albert Lai²  Linda M. Liau³  William H. Yong⁴  William H. McBride⁵  Jonathan L. Tso⁶  Alexandra Stream⁶  Yvonne Bui⁶  Jimmy C. Menjivar⁶  Irene Hong⁶  Kazunari Yamada⁷  Shuai Yang⁸  Yibei Zhang⁹  Cho-Lea Tso^1,10 

[1] Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;Department of Neurosurgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;Department of Radiation-Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Department of Advanced Molecular and Cell Therapy, Kyushu University Hospital, Higashiku, Fukuoka, Japan;Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Department of Neurosurgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China;Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Department of Orthopedics, Zhongshan Hospital, Xiamen University, Xiamen, China;Department of Surgery/Surgical Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, USA;

关键词: BMP7;    Glioblastoma;    Temozolomide;    MGMT;    Glioblastoma stem cells;   

DOI  :  10.1186/s12943-015-0459-1

 received in 2015-04-28, accepted in 2015-10-20,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundTemozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 μM).MethodsMGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 μM. Clonogenic GSC surviving 500 μM TMZ (GSC-500 μM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC.ResultsThe molecular signatures characterized an activation of protective stress responses in GSC-500 μM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 μM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 μM TMZ and GSC-parental to 35 μM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489).ConclusionsThese data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT.

【 授权许可】

CC BY   
© Tso et al. 2015