MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo

Ulasov, Ilya V.; Borovjagin, Anton V.; Kaverina, Natalya; Schroeder, Brett; Shah, Nameeta; Lin, Biaoyang; Baryshnikov, A. Yu.; Cobbs, Charles S.

doi:10.1016/j.canlet.2015.06.002

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…Unfortunately, only ~20% of all brain tumors are of primary origin at the time of diagnosis, while ~80% are metastatic (1). Gliomas are the most common primary brain tumor in adults and more than half are malignant (2).…”

Section: Introductionmentioning

confidence: 99%

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

Liu

Yang

et al. 2017

Oncol Lett

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Abstract. Gliomas are the most common type of primary brain tumor in adults, where more than half of the cases are malignant, and the prognosis is poor. The early viral 1A (E1A) protein has been widely recognized to be essential for adenoviral replication and production of progeny virions in human cells, a process that is regulated by human telomerase reverse transcriptase. The p53 gene, as a tumor suppressor, regulates diverse cellular processes, including cell cycle arrest, cell autophagy, senescence and apoptosis. Dysfunction of the p53 pathways is common in malignant gliomas. Exogenous expression of p53 during adenovirus replication in human cancer cells may accelerate cell death and improve the release of early virus progeny. In the present study, a conditionally replicative adenovirus (CRAd) Ad-Tp-E1A-Gp-p53, which expressed functional p53 protein when replicating in cancer cells, was constructed. Next, the level of p53 expression in U251 cells was determined by western blot analysis, and the inhibitory effect of Ad-Tp-E1A-Gp-p53 on U251 cells was detected via an MTT assay. The results indicated that p53 expression was upregulated with an increase in the multiplicity of infection (MOI) of Ad-Tp-E1A-Gp-p53. Additionally, the inhibitory effects of Ad-Tp-E1A-Gp-p53 in different groups were significantly different (P<0.05), with the inhibition ratio of the experimental groups being higher, compared with the control group (P<0.05). Furthermore, the inhibition ratio increased with increases in the MOI of Ad-Tp-E1A-Gp-p53. Therefore, the expression of functional p53 and that of E1A may increase the potency of CRAd, and overexpression of p53 through CRAd is a promising approach to more effective treatments in a number of human cancer types.

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Section: Introductionmentioning

confidence: 99%

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

Liu

Yang

et al. 2017

Oncol Lett

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“…This investigation should provide a more individualized stratification of GBM survival rates. Indeed, nuclear translocation of MMP14 after therapy was detected in neoplastic tissue of some GBM patients and would be an indication to introduce additional tumor treatment to reduce MMP14 driven glioma progression. Taking into consideration that increase in MMP14 has been reported during posttreatment recurrence of primary renal neuroblastoma and mammary phyllodes tumors, MMP14 surveillance becomes an important factor to examine in the decision‐making process regarding the antitumor treatments.…”

Section: Discussionmentioning

confidence: 99%

“…18 More recently, studies showed that MMP14 governs cell division, 19 proliferation 12 and angiogenesis in GBM, and suggested MMP14 as a target for improvement of the anti-glioma efficacy of TMZ/RT treatment. 20 The latter study also revealed that inhibition of MMP14 improves the survival of experimental animals with intracranially implanted U87 glioma cells without assessment of glioma heterogeneity and the responses of distinct tumor cell populations to therapy. 21,22 In the present study, we have investigated how MMP14 is involved in glioma progression and recurrence after the treatment with alkylating chemotherapy.…”

Section: Introductionmentioning

confidence: 97%

“…Subsequent studies detected MMP14 induction in response to TMZ/radiation therapy (RT) treatment in patients with GBM . More recently, studies showed that MMP14 governs cell division, proliferation and angiogenesis in GBM, and suggested MMP14 as a target for improvement of the anti‐glioma efficacy of TMZ/RT treatment . The latter study also revealed that inhibition of MMP14 improves the survival of experimental animals with intracranially implanted U87 glioma cells without assessment of glioma heterogeneity and the responses of distinct tumor cell populations to therapy …”

Section: Introductionmentioning

confidence: 99%

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TMZ regulates GBM stemness via MMP14‐DLL4‐Notch3 pathway

Ulasov

Mijanović

Savchuk

et al. 2019

Intl Journal of Cancer

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Glioblastoma (GBM) is one of the most aggressive primary brain tumors with frequent recurrences following the standard methods of treatment—temozolomide (TMZ), ionizing radiation and surgical resection. The objective of our study was to investigate GBM resistance mediated via MMP14 (matrix metalloproteinase 14). We used multiple PDX GBM models and established glioma cell lines to characterize expression and subcellular localization of MMP14 after TMZ treatment. We performed a Kiloplex ELISA‐based array to evaluate changes in cellular proteins induced by MMP14 expression and translocation. Lastly, we conducted functional and mechanistic studies to elucidate the role of DLL4 (delta‐like canonical notch ligand 4) in regulation of glioma stemness, particularly in the context of its relationship to MMP14. We detected that TMZ treatment promotes nuclear translocation of MMP14 followed by extracellular release of DLL4. DLL4 in turn stimulates cleavage of Notch3, its nuclear translocation and induction of sphering capacity and stemness.

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“…The inflammasome components, on complex scaffold protein assembly,29 trigger caspase activity and lead to the cleavage of precursors and release of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18 30. The MT1-MMP knockdown suppressed angiogenesis in glioma tumors through decreased production of pro-angiogenic factors, such as vascular endothelial growth factor and IL-8,31 and was also found to regulate the transcription of colony-stimulating factors 2 and 3 in mesenchymal stromal cells 8. In addition, MT1-MMP was also demonstrated to regulate caspase activity,32 angiogenesis,33 and cell migration 34.…”

Section: Introductionmentioning

confidence: 99%

A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression

Sheehy

Annabi

2017

Gene�Regul Syst Bio

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Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP’s role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP. To assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens with a transient MT1-MMP gene silencing strategy. Expression of MT1-MMP was found to exert both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as interleukin (IL)-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal-transducing pathways explored, the silencing of MT1-MMP prevented PMA from phosphorylating extracellular signal–regulated kinase, inhibitor of κB, and p105 nuclear factor κB (NF-κB) intermediates. We also found a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. Altogether, our data indicate a significant involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution to signal transduction functions in addition to its classical hydrolytic activity.

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MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo

Cited by 14 publications

References 41 publications

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

TMZ regulates GBM stemness via MMP14‐DLL4‐Notch3 pathway

A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression

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