Transcriptional and post‐transcriptional down‐regulation of cyclin D1 contributes to C6 glioma cell differentiation induced by forskolin

Abstract

Malignant gliomas are the most common and lethal intracranial tumors, and differentiation therapy shows great potential to be a promising candidate for their treatment. Here, we have elaborated that a PKA activator, forskolin, represses cell growth via cell cycle arrest in the G0/G1 phase and induces cell differentiation characteristic with elongated processes and restoration of GFAP expression. In mechanisms, we verified that forskolin significantly diminishes the mRNA and protein level of a key cell cycle regulator cyclin D1, and maintenance of low cyclin D1 expression level was required for forskolin-induced proliferation inhibition and differentiation by gain and loss of function approaches. In addition, that forskolin down-regulated the cyclin D1 by proteolytic (post-transcriptional) mechanisms was dependent on GSK-3β activation at Ser9. The pro-differentiation activity of forskolin and related molecular mechanisms imply that forskolin can be developed into a candidate for the future in differentiation therapy of glioma, and cyclin D1 is a promising target for pro-differentiation strategy.

Role of fucosyltransferase IV in epithelial–mesenchymal transition in breast cancer cells

“…Cyclin D was used as a positive control as it is subjected to GSK-3 β -dependent proteolysis. 34, 35, 36, 37, 38, 39 As anticipated, cyclin D expression increased when MCF-7 cells were treated with SB415286. To further ascertain the involvement of PI3K/Akt-GSK-3 β signaling in the FUT4 -induced acquisition of the mesenchymal phenotype, we used the alternative approach of transfecting pcDNA3.1- FUT4 into MCF-7 cells.…”

Conditioned Media from Human Adipose Tissue-Derived Mesenchymal Stem Cells and Umbilical Cord-Derived Mesenchymal Stem Cells Efficiently Induced the Apoptosis and Differentiation in Human Glioma Cell Lines In Vitro

“…Differentiation agents for malignant gliomas remain a real challenge. Some studies have shown arsenic trioxide (As 2 O 3 ) and forskolin can also trigger apoptosis and differentiation in glioma cells [39, 40]. In our study, we unexpectedly found a very strong differentiation effect of conditioned MSCs medium.…”

The Molecular Mechanism for Differentiation Therapy of Malignant Glioma

“…Accumulating evidences have reported that forskolin induces the differentiation of human monoblast U937 cells, neurocytoma cells and neuroblastoma x rat glioma cell line NG108-15 cells via elevating cAMP (Ammer&Schulz, 1997;Brodsky et al, 1998;Kim et al, 2004) , suggesting forskolin to be a potential candidate of differentiation inducing agents for glioma. In accordance with previous reports, forskolin represses cell growth via cell cycle arrest in the G0/G1 phase and induces cell differentiation characteristic with elongated processes and restoration of GFAP expression when administrated to malignant glioma C6 cells (Figure 6a and 6b) (Lu et al, 2009;He et al, 2011). In mechanisms, forskolin promotes C6 cell differentiation via regulating the transcription and proteolysis of cyclin D1, and maintenance of low cyclin D1 expression is required for its effects on differentiation as demonstrated by gain and loss of function studies (Figure 6c and 6d).…”