Protein kinase a, not Epac, suppresses Hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells
Protein kinase a, not Epac, suppresses Hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells
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DOI：
10.1074/jbc.m703697200
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发表时间：
2007-12-28
影响因子：
4.8
通讯作者：
Cheng, Xiaodong
中科院分区：
文献类型：
--
作者：
Ji, Zhenyu;Mei, Fang C.;Cheng, Xiaodong
环磷酸腺苷 (Cyclic AMP) 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。我们检查了 cAMP 依赖性蛋白激酶 (PKA) 和 Epac（由 cAMP 直接激活的交换蛋白）这两种细胞内 cAMP 受体在这种协同效应中发挥的各自作用。我们的研究表明，PKA 与 GC 具有协同作用，而 Epac 对 GC 诱导的细胞凋亡具有微弱的拮抗作用。我们发现 GC 敏感克隆的内源 PKA 活性高于 GC 抗性克隆。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通路特异性抑制剂抑制Hh活性会导致CEM（人急性淋巴细胞白血病，T谱系）细胞的细胞周期停滞和细胞凋亡，并且GC敏感克隆对Hh抑制更敏感。这些结果表明 Hh 活性对于白血病细胞的生长和存活至关重要，并且 Hh 活性水平部分负责 cAMP 和 GC 之间的协同作用。
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.