Decorin‐mediated inhibition of the migration of U87MG glioma cells involves activation of autophagy and suppression of TGF‐β signaling

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Abstract

Decorin ( DCN) is a major member of the small leucine‐rich proteoglycan ( SLRP) family that is critically involved in tumorigenesis and the development of metastasis of cancers, including glioma. Overexpression of DCN was indicated to suppress glioma cell growth. However, the role of DCN in the migration of glioma cells remain elusive. In this study, we found that treatment with exogenous DCN inhibited the adhesion and migration of U87 MG glioma cells with down‐regulation of TGF‐β signaling. DCN also activated autophagy, as indicated by monodansylcadaverine ( MDC) staining, increase in LC3 I/ LC3 II conversion, and p62/ SQSTM1 degradation in U87 MG cells. The increased activity of autophagy was found to be connected to the inhibition on glioma cell migration. Knockdown of DCN expression or the disruption of autophagy with 3‐methyladenine (3‐ MA) was able to reduce the suppression on cell adhesion and migration induced by DCN. When U87 MG cells were treated with temozolomide ( TMZ), induction of autophagy and up‐regulation of DCN were observed, accompanied by suppressed cell adhesion and migration. Transfection of si RNA targeting DCN attenuated the suppressive effect of TMZ on glioma cell migration and adhesion. Our results indicated that the migration of glioma cells was under the control of the active status of autophagy, with DCN serving as a key player, as well as an indicator of the outcome. Therefore, it is suggested that autophagy‐modulating reagents could be considered for the treatment of invasive glioma.

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Angiogenesis in brain tumours.

Rakesh Jain, Emmanuelle Di Tomaso, Dan G Duda … (2007)

Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.

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Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.

T Kanzawa, I Germano, T Komata … (2004)

Autophagy is originally named as a process of protein recycling. It begins with sequestering cytoplasmic organelles in a membrane vacuole called autophagosome. Autophagosomes then fuse with lysosomes, where the materials inside are degraded and recycled. To date, however, little is known about the role of autophagy in cancer therapy. In this study, we present that temozolomide (TMZ), a new alkylating agent, inhibited the viability of malignant glioma cells in a dose-dependent manner and induced G2/M arrest. At a clinically achievable dose (100 microM), TMZ induced autophagy, but not apoptosis in malignant glioma cells. After the treatment with TMZ, microtubule-associated protein light-chain 3 (LC3), a mammalian homologue of Apg8p/Aut7p essential for amino-acid starvation-induced autophagy in yeast, was recruited on autophagosome membranes. When autophagy was prevented at an early stage by 3-methyladenine, a phosphatidylinositol 3-phosphate kinase inhibitor, not only the characteristic pattern of LC3 localization, but also the antitumor effect of TMZ was suppressed. On the other hand, bafilomycin A1, a specific inhibitor of vacuolar type H(+)-ATPase, that prevents autophagy at a late stage by inhibiting fusion between autophagosomes and lysosomes, sensitized tumor cells to TMZ by inducing apoptosis through activation of caspase-3 with mitochondrial and lysosomal membrane permeabilization, while LC3 localization pattern stayed the same. These results indicate that TMZ induces autophagy in malignant glioma cells. Application of an autophagy inhibitor that works after the association of LC3 with autophagosome membrane, such as bafilomycin A1, is expected to enhance the cytotoxicity of TMZ for malignant gliomas.

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A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

Myrna R Rosenfeld, Xiaobu Ye, Jeffrey Supko … (2014)

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

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Author and article information

Journal

Journal ID (nlm-ta): FEBS Open Bio

Journal ID (iso-abbrev): FEBS Open Bio

Journal ID (doi): 10.1002/(ISSN)2211-5463

Journal ID (publisher-id): FEB4

Title: FEBS Open Bio

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2211-5463

Publication date (Electronic): 31 May 2016

Publication date Collection: July 2016

Volume: 6

Issue: 7 ( doiID: 10.1111/feb4.2016.6.issue-7 )

Pages: 707-719

Affiliations

[ ¹ ] Department of Medical Genetics and Developmental BiologyCapital Medical University BeijingChina

[ ² ] Department of Biochemistry and Molecular BiologyCapital Medical University BeijingChina

[ ³ ] Beijing Key Laboratory for Researches in Cancer Invasion and MetastasisCancer Institute of Capital Medical University BeijingChina

[ ⁴ ] Department of NeurosurgeryBeijing Tiantan Hospital China

[ ⁵ ]Beijing Institute of Brain Disorders China

Author notes

[*] [* ] Correspondence

W. Ding, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China

Fax: +86 10 8391 1496

Tel: +86 10 8391 1694

E‐mail: weiding@ 123456ccmu.edu.cn

[†]

These authors contributed equally to this work

Article

Publisher ID: FEB412076

DOI: 10.1002/2211-5463.12076

PMC ID: 4932450

PubMed ID: 27398310

SO-VID: 071f018e-826b-4109-a336-1a2ff8c73cc6

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 10 March 2016

Date revision received : 18 April 2016

Date accepted : 19 April 2016

Page count

Pages: 13

Funding

Funded by: Natural Science Foundation of China

Award ID: 81372284

Award ID: 81201816

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component-id feb412076

cover-date July 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:05.07.2016

Decorin‐mediated inhibition of the migration of U87MG glioma cells involves activation of autophagy and suppression of TGF‐β signaling

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Most cited references 39

Angiogenesis in brain tumours.

Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme

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