Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells.
Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells.
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DOI：
10.1186/1475-2867-7-3
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发表时间：
2007-03-28
影响因子：
5.8
通讯作者：
Thompson EB
中科院分区：
文献类型：
--
作者：
Miller AL;Garza AS;Johnson BH;Thompson EB
糖皮质激素经常被用作许多类型的人类淋巴恶性肿瘤的主要化疗剂，因为它们通过激活糖皮质激素受体诱导细胞凋亡，随后改变复杂的细胞机制网络。尽管糖皮质激素的临床应用已有50多年，但糖皮质激素相关的细胞凋亡或耐药的完整机制仍然难以捉摸。丝裂原活化蛋白激酶途径是一种信号转导网络，通过特异性靶底物（包括糖皮质激素受体）的磷酸化影响多种细胞反应。在这项研究中，我们已经评估了药物的情况下，收敛于丝裂原活化蛋白激酶途径，以改变糖皮质激素的敏感性克隆的人急性淋巴母细胞CEM细胞敏感性和难治性细胞凋亡的合成糖皮质激素地塞米松。糖皮质激素抗性克隆CEM-C1-15显示出高组成性JNK活性和地塞米松诱导的ERK活性的组合，糖皮质激素处理后p38的诱导较弱。在以下情况下，细胞变得对糖皮质激素诱发的凋亡敏感：（1）抑制JNK和ERK活性，（2）用毛喉素刺激cAMP/PKA途径，或（3）用雷帕霉素抑制mTOR。与地塞米松组合的治疗1-3通过降低JNK磷酸化和增加在丝氨酸211处磷酸化的糖皮质激素受体的水平（一种已知增强受体活性的修饰）来改变磷酸-MAPK的细胞内平衡。我们的数据支持这一假设，即有丝分裂原活化蛋白激酶影响某些恶性淋巴细胞的能力进行细胞凋亡时，糖皮质激素治疗。活化/磷酸化的JNK和ERK似乎抵消皮质激素依赖性细胞凋亡。抑制这些MAPK恢复皮质激素对CEM细胞的抗性克隆的敏感性。激活cAMP通路的毛喉素和抑制mTOR的雷帕霉素也抑制JNK。此外，致敏处理导致在丝氨酸211处磷酸化的糖皮质激素受体的总库的主要地塞米松依赖性增加。已知磷酸丝氨酸211受体在激活基因转录和凋亡中更有效。在此证明的将耐药细胞恢复为皮质激素敏感性的相互作用可以在淋巴恶性肿瘤的治疗中提供治疗临床潜力。
Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. The glucocorticoid-resistant clone CEM-C1-15 displays a combination of high constitutive JNK activity and dexamethasone-induced ERK activity with a weak induction of p38 upon glucocorticoid treatment. The cells become sensitive to glucocorticoid-evoked apoptosis after: (1) inhibition of JNK and ERK activity, (2) stimulation of the cAMP/PKA pathway with forskolin, or (3) inhibition of mTOR with rapamycin. Treatments 1–3 in combination with dexamethasone alter the intracellular balance of phospho-MAPKs by lowering JNK phosphorylation and increasing the level of glucocorticoid receptor phosphorylated at serine 211, a modification known to enhance receptor activity. Our data support the hypothesis that mitogen-activated protein kinases influence the ability of certain malignant lymphoid cells to undergo apoptosis when treated with glucocorticoid. Activated/phosphorylated JNK and ERK appear to counteract corticoid-dependent apoptosis. Inhibiting these MAPKs restores corticoid sensitivity to a resistant clone of CEM cells. Forskolin, which activates the cAMP pathway, and rapamycin, which inhibits mTOR, also inhibit JNK. Further, the sensitizing treatments result in a largely dexamethasone-dependent increase in the total pool of glucocorticoid receptor phosphorylated at serine 211. The phospho-serine 211 receptor is known to be more potent in activating gene transcription and apoptosis. The interactive effects demonstrated here in reverting resistant cells to corticoid sensitivity could provide therapeutic clinical potential in the treatment of lymphoid malignancies.
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影响因子：
20.3
作者：
Gururajan, M;Chui, R;Bondada, S
通讯作者：
Bondada, S
影响因子：
--
作者：
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通讯作者：
Thompson, EB
影响因子：
3.5
作者：
Sommer, A;Burkhardt, H;Lüscher, B
通讯作者：
Lüscher, B
影响因子：
5.3
作者：
BAKER, SJ;KERPPOLA, TK;ABATE, C
通讯作者：
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影响因子：
8
作者：
Hideshima, T;Hayashi, T;Anderson, K
通讯作者：
Anderson, K