Cyclic AMP-Response Element Regulated Cell Cycle Arrests in Cancer Cells

Abstract

Recently, we have demonstrated that trichosanthin (TCS), a promising agent for the treatment of cervical adenocarcinoma, inhibited HeLa cell proliferation through the PKC/MAPK/CREB signal pathway. Furthermore, TCS down-regulated Bcl-2 expression was abrogated by a decoy oligonucleotide (OGN) to the cyclic AMP-responsive element (CRE). The decoy OGN blocked the binding of CRE-binding protein (CREB) to Bcl-2. These results suggested that CRE-mediated gene expression may play a pivotal role in HeLa cell proliferation. However, little is known about the effect of TCS on cell cycle arrests, particularly, whether the genes involved in cell cycle were regulated by CRE. Our present study shows that the arrests of S, G1 and G2/M phases were accompanied by the significant down-regulation of cyclin A, D1 and CDK 2, 4 in HeLa cells, cyclin D1, E and CDK 2, 4 in Caski and C33a cells, and cyclin A, B1, E and CDK 2 in SW1990 cells. However, the cell cycle arrests were reversed via the significant up-regulation of cyclin A and D1, by the combined treatment of TCS and CRE. In conclusion, these data demonstrate for the first time that specific cell cycle arrests in cancer cells can be induced by TCS by inhibiting the binding of CREB to CRE on genes related to cell proliferation.

The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo

“…Overall, selenite decreases the Bcl-2 expression by inhibiting the transcriptional activity of CREB in CRC cells. It has been reported that CREB regulates Bcl-2 expression in other cancer cells, such as non-small cell lung cancer (NSCLC) cell lines, MCF7 breast cancer cells and HeLa cell lines, which is consistent with our conclusion [8,13,34].…”

“…In the nucleus, activated CREB can bind to promoters containing a consensus sequence to enhance the transcription of various survival proteins including Bcl-2 [8,16,18,22]. Bcl-2 family proteins are essential regulators of selenite-induced apoptosis [23][24][25].…”

“…The cyclic adenosine monophosphate (cAMP) response elementbinding protein (CREB) is necessary for the proliferation, growth, survival, and differentiation of many cell types [8]. Recent research has demonstrated that CREB regulates the expression of a repertoire of genes associated with cell survival, such as Bcl-2, Bcl-xL, c-fos and tumour necrosis factor-α (TNF-α) [9][10][11][12].…”

Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer

“…Several reports have revealed that CREB phosphorylation is necessary for cell survival [7], promoting tumorigenesis in NSCLC, breast cancer [8,9], acute myeloid leukemia [10,11], hepatocellular carcinoma [12,13], glioma or for gliomagenesis [14,15] and tumor metastasis of melanoma cells [16,17]. Taken together with our previous reports that a cyclic-AMP-responsive element (CRE, TGACGTCA) decoy oligonucleotide blocked the CREB binding site on Bcl-2 [18,19] and cyclins [20] can abrogate antitumor drug-induced apoptosis and cell proliferation, it was suggested that CREB plays a key role in tumor progression. Nonetheless, the possible role of constitutively active CREB at Ser 133 (phosphorylated CREB [pCREB]) in the growth and metastasis of RCC has been little investigated.…”

Hypoxia-induced apoptosis and mitochondrial dysfunction in chondrocytes arising from CREB phosphorylation reduction

“…Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is necessary for cell proliferation and apoptosis (Wang et al, 2013) because it regulates the expression of a repertoire of genes associated with cell survival. Those genes include B-cell lymphoma 2 (BCL2), B-cell lymphoma-extra large (BCLXL), and CFOS (Ferron et al, 2011;Han et al, 2013), and are particularly relevant during hypoxia (Meng et al, 2012).…”