Li Yan, Yin Wei, Wang Xia, Zhu Wenbo, Huang Yijun, Yan Guangmei
Department of Pharmacology, Zhong-shan Medical College, Sun Yat-Sen University, Guangzhou 510089, China.
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13438-43. doi: 10.1073/pnas.0701990104. Epub 2007 Aug 6.
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 G(1) phase of the cell cycle. Cholera toxin also triggered a significant reduction in the G(1) cell-cycle regulatory proteins cyclin D1 and Cdk2 along with an overexpression of cell-cycle inhibitory proteins p21(Cip1) and p27(Kip1). 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.
恶性胶质瘤是全球癌症死亡的主要原因之一，但针对它们的化学预防策略却很少且研究不足。在此，我们表明，霍乱毒素这种传统生物毒素以及众所周知的细胞内环磷酸腺苷（cAMP）积累诱导剂，能够在体外诱导大鼠C6和原代培养的人胶质瘤细胞发生恶性胶质瘤分化。霍乱毒素诱导的分化表现为典型的形态学变化、胶质纤维酸性蛋白表达增加、Ki-67表达降低、细胞增殖受到抑制以及细胞在细胞周期的G(1)期积累。霍乱毒素还引发了G(1)期细胞周期调节蛋白细胞周期蛋白D1和细胞周期蛋白依赖性激酶2（Cdk2）的显著减少，同时细胞周期抑制蛋白p21(Cip1)和p27(Kip1)过表达。蛋白激酶A抑制剂消除cAMP依赖性蛋白激酶A活性或RNA干扰使cAMP反应元件结合蛋白沉默，均导致分化受到抑制。这些发现表明霍乱毒素作为进一步开发分化疗法的候选药物具有吸引力。此外，蛋白激酶A/cAMP反应元件结合蛋白途径的激活可能是胶质瘤分化的关键且必要因素。
