Transcriptional upregulation of microtubule-associated protein 2 is involved in the protein kinase A-induced decrease in the invasiveness of glioma cells
research target：glioma cells
Periodicals：Neuro-Oncology
IF：7.371
Cooperative Unit：Sun Yat-sen University Zhongshan Medical College, The Third Affiliated Hospital of Sun Yat-sen University
Time of publication：May 25, 2015
Summary
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.
1.Effects of protein kinase A (PKA) activators on the morphology of malignant glioma cells. C6, DBTRG-05MG, and A172 glioma were used to test the effects of PKA activators (1 mM dbcAMP, 10 ng/mL cholera toxin, and 30 µM forskolin). Cells (1×105) were seeded in 24-well plates and incubated with different kinds of PKA activators for 48 hours (original magnification:×100; scale bar: 100 µm)
2.Suppressive effects of protein kinase A (PKA) activators on migration and invasion of malignant glioma cells.
3.Disruption of microtubule dynamic instability by protein kinase A (PKA) pathway.
4.Positive modulation of low-molecular-weight MAP2 by PKA activation.
5.Transcriptional upregulation of MAP2 expression involved PKA-induced decreased invasion of glioma cells.
6.Representative effects of dbcAMP on human glioblastoma (GBM) primary cultures.
References
Zhou Y, Wu S, Liang C, et al. Transcriptional upregulation of microtubule-associated protein 2 is involved in the protein kinase A-induced decrease in the invasiveness of glioma cells.[J]. Neuro-oncology, 2015.
