Targeting extracellular matrix remodeling sensitizes glioblastoma to ionizing radiation

被引:6
作者
Thakur, Varsha [1 ,2 ]
Thakur, Vijay S. [2 ,3 ]
Aguila, Brittany [2 ,3 ]
Slepak, Tatiana, I [4 ]
Wang, Man [5 ]
Song, Wei [5 ]
Konai, Mohini [5 ]
Mobashery, Shahriar [5 ]
Chang, Mayland [5 ]
Rana, Ayush B. [2 ,3 ]
Wang, Dazhi [2 ,3 ]
de Freitas, Juliano Tiburcio [1 ,2 ]
Gultekin, Sakir Humayun [6 ]
Welford, Scott M. [2 ,3 ]
Ivan, Michael E. [4 ]
Bedogni, Barbara [1 ,2 ]
机构
[1] Univ Miami, Miller Sch Med, Phillip Frost Dept Dermatol & Cutaneous Surg, Miami, FL 33136 USA
[2] Sylvester Comprehens Canc Ctr, Miami, FL USA
[3] Univ Miami, Miller Sch Med, Dept Radiat Oncol, Miami, FL 33136 USA
[4] Univ Miami, Miller Sch Med, Dept Neurol Surg, Miami, FL 33136 USA
[5] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[6] Univ Miami, Miller Sch Med, Neuropathol, Div Anat Pathol, Miami, FL 33136 USA
关键词
GBM; MT1-MMP; (R)-ND336; radiation resistance; radio-sensitization; INHIBITOR; ACTIVATION; METALLOPROTEINASE-2; CONTRIBUTES; EXPRESSION; BINDING; PROTEIN; GROWTH; ROLES; PHASE;
D O I
10.1093/noajnl/vdac147
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background The median survival of Glioblastoma multiforme (GBM) patients is 14+ months due to poor responses to surgery and chemoradiation. Means to counteract radiation resistance are therefore highly desirable. We demonstrate the membrane bound matrix metalloproteinase MT1-MMP promotes resistance of GBM to radiation, and that using a selective and brain permeable MT1-MMP inhibitor, (R)-ND336, improved tumor control can be achieved in preclinical studies. Methods Public microarray and RNA-sequencing data were used to determine MT1-MMP relevance in GBM patient survival. Glioma stem-like neurospheres (GSCs) were used for both in vitro and in vivo assays. An affinity resin coupled with proteomics was used to quantify active MT1-MMP in brain tissue of GBM patients. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP and inhibition via the MT1-MMP inhibitor (R)-ND336, were used to assess the role of MT1-MMP in radio-resistance. Results MT1-MMP expression inversely correlated with patient survival. Active MT1-MMP was present in brain tissue of GBM patients but not in normal brain. shRNA- or (R)-ND336-mediated inhibition of MT1-MMP sensitized GSCs to radiation leading to a significant increase in survival of tumor-bearing animals. MT1-MMP depletion reduced invasion via the effector protease MMP2; and increased the cytotoxic response to radiation via induction of replication fork stress and accumulation of double strand breaks (DSBs), making cells more susceptible to genotoxic insult. Conclusions MT1-MMP is pivotal in maintaining replication fork stability. Disruption of MT1-MMP sensitizes cells to radiation and can counteract invasion. (R)-ND336, which efficiently penetrates the brain, is therefore a novel radio-sensitizer in GBM.
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页数:14
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