Ji Zhenyu, Mei Fang C, Johnson Betty H, Thompson E Brad, Cheng Xiaodong
Department of Pharmacology and Toxicology, School of Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA.
J Biol Chem. 2007 Dec 28;282(52):37370-7. doi: 10.1074/jbc.M703697200. Epub 2007 Sep 25.
Cyclic AMP synergizes strongly with glucocorticoids (GC) to induce apoptosis in normal or malignant lymphoid cells. We examined the individual roles that cAMP-dependent protein kinase (PKA) and Epac (exchange protein directly activated by cAMP), two intracellular cAMP receptors, play in this synergistic effect. Our studies demonstrate that PKA is responsible for the observed synergism with GC, whereas Epac exerts a weak antagonistic effect against GC-induced apoptosis. We find that endogenous PKA activity is higher in the GC-sensitive clone than in the GC-resistant clone. In the GC-sensitive clone, higher PKA activity is associated with lower Hedgehog (Hh) activity. Moreover, inhibition of Hh activity by Hh pathway-specific inhibitors leads to cell cycle arrest and apoptosis in CEM (human acute lymphoblastic leukemia, T lineage) cells, and the GC-sensitive clone is more sensitive to Hh inhibition. These results suggest that Hh activity is critical for leukemia cell growth and survival and that the level of Hh activity is in part responsible for the synergism between cAMP and GC.
环磷酸腺苷（cAMP）与糖皮质激素（GC）强烈协同作用，诱导正常或恶性淋巴细胞凋亡。我们研究了两种细胞内cAMP受体，即cAMP依赖性蛋白激酶（PKA）和直接由cAMP激活的交换蛋白（Epac），在这种协同效应中所起的各自作用。我们的研究表明，PKA是观察到的与GC协同作用的原因，而Epac对GC诱导的凋亡发挥微弱的拮抗作用。我们发现，GC敏感克隆中的内源性PKA活性高于GC耐药克隆。在GC敏感克隆中，较高的PKA活性与较低的Hedgehog（Hh）活性相关。此外，Hh信号通路特异性抑制剂对Hh活性的抑制导致CEM（人急性淋巴细胞白血病，T细胞系）细胞的细胞周期停滞和凋亡，且GC敏感克隆对Hh抑制更敏感。这些结果表明，Hh活性对白血病细胞的生长和存活至关重要，且Hh活性水平部分地导致了cAMP与GC之间的协同作用。
