Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
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DOI：
10.1172/jci34764
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发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Abate-Shen, Cory
中科院分区：
文献类型：
--
作者：
Kinkade, Carolyn Waugh;Castillo-Martin, Mireia;Abate-Shen, Cory
AKT/哺乳动物雷帕霉素靶蛋白（AKT/mTOR）和ERK MAPK信号通路已被证明在前列腺癌进展和向雄激素非依赖性疾病的转变中协同作用。我们现在已经测试了组合抑制这些途径对前列腺致瘤性的影响，通过使用基因工程小鼠前列腺癌模型进行临床前研究。我们在这里报告，使用雷帕霉素，mTOR的抑制剂，和PD 0325901，MAPK激酶1（MEK; ERK的直接上游的激酶）的抑制剂，抑制细胞生长培养的前列腺癌细胞细颗粒和肿瘤生长，特别是雄激素非依赖性前列腺肿瘤在小鼠模型中的联合治疗。我们进一步表明，这种抑制导致增殖抑制和细胞凋亡调节因子Bcl-2相互作用的细胞死亡介质（Bim）的表达上调。此外，人前列腺癌组织微阵列的分析表明，AKT/mTOR和ERK MAPK信号通路通常在人类前列腺癌进展期间协同失调。因此，我们建议靶向AKT/mTOR和ERK MAPK信号通路的联合治疗可能是晚期前列腺癌患者的有效治疗方法，特别是那些患有难治性疾病的患者。
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell fines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.