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Cholera toxin induces malignant glioma cell differentiation via the PKA/CREB pathway
Yan Li*, Wei Yin
, Xia Wang*, Wenbo Zhu*, Yijun Huang*, and Guangmei Yan*,
Departments of *Pharmacology and Biochemistry, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou 510089, China
Edited by John J. Mekalanos, Harvard Medical School, Boston, MA, and approved July 5, 2007 (received for review March 14, 2007)
Malignant gliomas are one of the leading causes of cancer deaths worldwide, but chemoprevention strategies for them are few and poorly investigated. Here, we show that cholera toxin, the traditional biotoxin and well known inducer of accumulation of cellular cAMP, is capable of inducing differentiation on malignant gliomas in vitro with rat C6 and primary cultured human glioma cells. Cholera toxin-induced differentiation was characterized by typical morphological changes, increased expression of glial fibrillary acid protein, decreased expression of Ki-67, inhibition of cellular proliferation, and accumulation of cells in the G1 phase of the cell cycle. Cholera toxin also triggered a significant reduction in the G1 cell-cycle regulatory proteins cyclin D1 and Cdk2 along with an overexpression of cell-cycle inhibitory proteins p21Cip1 and p27Kip1. Abrogation of cAMP-dependent protein kinase A activity by protein kinase A inhibitor or silencing of cAMP-responsive element binding proteins by RNA interference resulted in suppressed differentiation. These findings imply the attractiveness of cholera toxin as a drug candidate for further development of differentiation therapy. Furthermore, activation of the protein kinase A/cAMP-responsive element binding protein pathway may be a key and requisite factor in glioma differentiation.
