ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK).
ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK).
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DOI：
10.1016/j.urolonc.2003.12.012
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
J. Aguirre-Ghiso;Y. Estrada;David Liu;L. Ossowski
中科院分区：
文献类型：
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作者：
J. Aguirre-Ghiso;Y. Estrada;David Liu;L. Ossowski
在从原发性肿瘤扩散后，癌细胞可能恢复生长，导致明显的转移，或进入长期休眠状态。然而，决定其命运的机制或预测其命运的标志物大多不可用。我们以前的研究表明，在HEp 3人头颈癌中，细胞外信号调节激酶（ERK）MAPK/p38 SAPK活性比值可预测细胞是否会在体内增殖或进入休眠状态。尿激酶（uPA）受体（uPAR）高表达激活α5β1-整合素和表皮生长因子受体，诱导ERK/p38高比例的促增殖平衡。uPA结合uPAR和纤连蛋白结合α5β1-整联蛋白可进一步增强该信号通路。我们测试了ERK/p38平衡是否可以预测其他类型癌细胞的体内行为，以及改变这种平衡是否会使它们的表型在增殖和休眠之间转变。使用磷酸化特异性单克隆抗体或atrans报告系统测定ERK和p38活性，其中荧光素酶基因的GAL 4-Elk和GAL 4-CHOP反式激活分别作为ERK和p38活性的报告基因。我们发现，在乳腺癌、前列腺癌、黑色素瘤和纤维肉瘤细胞系中，活性磷酸化ERK水平和ERK/p38活性比预测了约90%的受试细胞系的体内行为。通过多种药理学和遗传学干预对ERK/p38活性比率的调节证实了高ERK/p38比率有利于肿瘤生长，而高p38/ERK比率诱导体内肿瘤生长停滞（休眠），并且ERK受p38负调控。黑色素瘤细胞系似乎已经开发出一种逃避机制，以避免高p38活性的生长抑制作用。机制分析表明，在几种细胞系中，高uPAR表达及其与α5β1-整合素的相互作用和激活是促进高ERK/p38比率的决定因素。小的GTdR，Cdc 42，涉及p38的激活和生长停滞。这些结果表明，即使是起源于晚期癌症的细胞也保留了一定程度的依赖于表面受体和基质的增殖信号，并提供了一个治疗机会，将其表型从致瘤性转变为休眠。
After dissemination from a primary tumor, cancer cells may resume growth, leading to overt metastasis, or enter a state of protracted dormancy. However, mechanisms that determine their fate, or markers that predict it, are mostly unavailable. We previously showed that in HEp3 human head and neck carcinoma, the extracellular signal-regulated kinase (ERK)MAPK/p38SAPKactivity ratio predicts whether the cells will proliferate or enter a state of dormancyin vivo. The proproliferative balance of high ERK/p38 ratio was induced by high urokinase (uPA) receptor (uPAR) expression, which activated α5β1-integrin and epidermal growth factor receptor. This signaling pathway was additionally enhanced by uPA binding to uPAR and fibronectin binding to α5β1-integrin. We tested whether the ERK/p38 balance is predictive ofin vivobehavior in other cancer cell types and whether altering the balance will shift their phenotype between proliferation and dormancy. ERK and p38 activities were determined using either phospho-specific monoclonal antibodies or atrans-reporting system where GAL4-Elk and GAL4-CHOPtrans-activation of luciferase gene served as reporters for ERK and p38 activities, respectively. We show that in breast, prostate, melanoma, and fibrosarcoma cell lines, the level of active phospho-ERK and the ERK/p38 activity ratio predict for thein vivobehavior in ∼90% of the cell lines tested. Modulation of ERK/p38 activity ratio by multiple pharmacological and genetic interventions confirms that high ERK/p38 ratio favors tumor growth, whereas high p38/ERK ratio induces tumor growth arrest (dormancy)in vivoand that ERK is negatively regulated by p38. A melanoma cell line appeared to have developed an escape mechanism to avoid the growth inhibitory effect of high p38 activity. Mechanistic analysis implicated high uPAR expression and its interaction with and activation of α5β1-integrin as determinants of thein vivogrowth promoting high ERK/p38 ratio in several cell lines. The small GTPase, Cdc42, was implicated in activation of p38 and growth arrest. These results suggest that even cells that originate in advanced cancers retain a degree of dependence on surface receptors and matrix for their proliferative signalsin vivoand provide a therapeutic opportunity to change their phenotype from tumorigenic to dormant.