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.
Highlights
Trichosanthin (TCS), an active component isolated from the root tubers of the Chinese medicinal herb Trichosanthes kirilowii [1], is a promising agent for the treatment of cancer [2]
Little is known about the effect of TCS on cell cycle arrest of HeLa cell, cervical squamous carcinoma (Caski and C33a cell), and human pancreatic carcinoma (SW1990 cell), especially, whether genes related to cell cycle were regulated by the cyclic AMP-responsive element (CRE) decoy OGN
Dose-dependent cell number increases of S, G1, G2/M phase were shown in HeLa, Caski, and SW1990 cells respectively, after they were treated for 24 hours, (Table 2)
Summary
Trichosanthin (TCS), an active component isolated from the root tubers of the Chinese medicinal herb Trichosanthes kirilowii [1], is a promising agent for the treatment of cancer [2]. TCS down-regulated Bcl-2 expression [5], which was abrogated by a cyclic AMP-responsive element (CRE, TGACGTCA) decoy oligonucleotide (OGN), blocking the CRE-binding protein (CREB) binding site on Bcl-2 [6]. These results suggest that CRE-mediated gene expression may play a pivotal role in HeLa cell proliferation. We further explored the effects of TCS on the proliferation of cancer cells, cell cycle arrests in the progress of cell proliferation and the role of CRE in cell cycle regulation Little is known about the effect of TCS on cell cycle arrest of HeLa cell, cervical squamous carcinoma (Caski and C33a cell), and human pancreatic carcinoma (SW1990 cell), especially, whether genes related to cell cycle were regulated by the CRE decoy OGN.
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