Abstract
Resistance to temozolomide (TMZ) is a major clinical challenge in glioma treatment, but the mechanisms of TMZ resistance are poorly understood. Here, we provided evidence that ROCK2 acted redundantly to maintain resistance of TMZ in TMZ-resistant gliomas, and as a ROCK2 phosphorylation inhibitor, fasudil significantly suppressed proliferation of TMZ-resistant gliomas in vivo and vitro via enhancing the chemosensitivity of TMZ. Additionally, the membrane translocation of ABCG2 was decreased with fasudil by ROCK2/moesin pathway. We also showed that fasudil suppressed the expression of ABCG2 via ROCK2/moesin/β-catenin pathway. Our results reveal an indispensable role for ROCK2 and provide strong evidence for the therapeutic use of fasudil in the clinical setting for TMZ-resistant gliomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / administration & dosage
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Drug Synergism
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Glioma / drug therapy*
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Glioma / metabolism
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Glioma / pathology
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Humans
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Rats
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Temozolomide / administration & dosage
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Temozolomide / pharmacology*
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rho-Associated Kinases / antagonists & inhibitors*
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rho-Associated Kinases / metabolism
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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Neoplasm Proteins
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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ROCK2 protein, human
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rho-Associated Kinases
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fasudil
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Temozolomide