We have reported previously that activation of cAMP/protein kinase A (PKA) pathway is capable of inducing glioma cell differentiation, characterized by astrocyte-like shape and dramatic induction of astrocyte biomarker glial fibrillary acidic protein (GFAP). However, little progress has been made on molecular mechanisms related.
Here we demonstrate that microRNA 335 (miR-335) is responsible for the glioma cell differentiation stimulated by activation of cAMP/PKA pathway.
In the cAMP elevator cholera toxin-induced differentiation model of rat C6 glioma cells, miR-335 was significantly up-regulated, which was mimicked by other typical cAMP/PKA pathway activators (e.g., forskolin, dibutyryl-cAMP) and abolished by PKA-specific inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i] [1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). In an assay measuring gain and loss of miR-335 function, exogenetic miR-335 resulted in induction of GFAP, whereas miR-335 specific inhibitor antagomir-335 violently blocked cholera toxin-induced GFAP up-regulation. It is noteworthy that in human U87-MG glioma cells and human primary culture glioma cells, miR-335 also mediated cholera toxin-induced differentiation.
Taken together, our findings suggest that miR-335 is potently required for differentiation of malignant glioma cells induced by cAMP/PKA pathway activation, and a single microRNA may act as an important fate determinant to control the differentiation status of malignant gliomas, which has provided a new insight into differentiation-inducing therapy against malignant gliomas.
Mol Pharmacol (1521-0111)
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China.
Mol Pharmacol. 2012 Mar;81(3):292-8
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