title: Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas.
abstract: Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy.
authors.affiliation: The Brain Tumor Center, The University of Chicago Chicago, Illinois, 60637.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ulasov
authors.forename: Bart
authors.initials: B
authors.lastname: Thaci
authors.forename: Purvaba
authors.initials: P
authors.lastname: Sarvaiya
authors.forename: Ruiyang
authors.initials: R
authors.lastname: Yi
authors.forename: Donna
authors.initials: D
authors.lastname: Guo
authors.forename: Brenda
authors.initials: B
authors.lastname: Auffinger
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.forename: Anton
authors.initials: A
authors.lastname: Borovjagin
authors.forename: Mahua
authors.initials: M
authors.lastname: Dey
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.forename: Anatoly Y
authors.initials: AY
authors.lastname: Baryshnikov
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D034622:RNA Interference; D011827:Radiation; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; C587995:MIRN374 microRNA 374, human; D035683:MicroRNAs; D003606:Dacarbazine; D053511:Matrix Metalloproteinase 14; D000077204:Temozolomide
keywords: Brain cancer; MMP14; glioma; radiation; temozolomide