Yuxi Zhou1, Sihan Wu1, Chaofeng Liang1, Yuan Lin1, Yan Zou1, Kai Li1, Bingzheng Lu1, Minfeng Shu1, Yijun Huang1, Wenbo Zhu1, Zhuang Kang1, Dong Xu1, Jun Hu1, Guangmei Yan1. 1. Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (Y.Z., S.W., Y.L., K.L., B.L., M.S., Y.H., W.Z., D.X., J.H., G.Y.); Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (C.L.); Department of Imaging, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Y.Z., Z.K.); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (J.H.).
Abstract
BACKGROUND: Malignant glioma is the most lethal primary tumor of the central nervous system, with notable cell invasion causing significant recurrence. Suppression of glioma invasion is very important for improving clinical outcomes. Drugs that directly disrupt the cytoskeleton have been developed for this purpose; however, drug resistance and unsatisfactory selectivity have limited their clinical use. Previously, we reported that protein kinase A (PKA, also known as cyclic-AMP dependent protein kinase) activation induced the differentiation of glioma cells. METHODS: We used several small molecular inhibitors and RNA interference, combined with wound healing assays, Matrigel transwell assay, and microscopic observation, to determine whether activation of the PKA pathway could inhibit the invasion of human glioma cells. RESULTS: Activation of PKA decreased the invasion of glioma cells. The mechanism operated via transcriptional upregulation of microtubule-associated protein 2 (MAP2), which was activated by the PKA pathway and led to ossification of microtubule dynamics via polymerization of tubulin. This resulted in morphological changes and a reduction in glioma cell invasion. Furthermore, chromosome immunoprecipitation and quantitative real-time polymerase chain reaction showed that signal transducer and activator of transcription 3 (STAT3) is involved in the transcriptional upregulation of MAP2. CONCLUSION: Our findings suggested that PKA may represent a potential target for anti-invasion glioma therapy and that the downstream modulators (eg, STAT3/MAP2) partially mediate the effects of PKA.
BACKGROUND:Malignant glioma is the most lethal primary tumor of the central nervous system, with notable cell invasion causing significant recurrence. Suppression of glioma invasion is very important for improving clinical outcomes. Drugs that directly disrupt the cytoskeleton have been developed for this purpose; however, drug resistance and unsatisfactory selectivity have limited their clinical use. Previously, we reported that protein kinase A (PKA, also known as cyclic-AMP dependent protein kinase) activation induced the differentiation of glioma cells. METHODS: We used several small molecular inhibitors and RNA interference, combined with wound healing assays, Matrigel transwell assay, and microscopic observation, to determine whether activation of the PKA pathway could inhibit the invasion of humanglioma cells. RESULTS: Activation of PKA decreased the invasion of glioma cells. The mechanism operated via transcriptional upregulation of microtubule-associated protein 2 (MAP2), which was activated by the PKA pathway and led to ossification of microtubule dynamics via polymerization of tubulin. This resulted in morphological changes and a reduction in glioma cell invasion. Furthermore, chromosome immunoprecipitation and quantitative real-time polymerase chain reaction showed that signal transducer and activator of transcription 3 (STAT3) is involved in the transcriptional upregulation of MAP2. CONCLUSION: Our findings suggested that PKA may represent a potential target for anti-invasion glioma therapy and that the downstream modulators (eg, STAT3/MAP2) partially mediate the effects of PKA.
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