Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells
Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells
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DOI：
10.1158/0008-5472.can-06-0802
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Lu, Bo
中科院分区：
文献类型：
--
作者：
Cao, Carolyn;Subhawong, Ty;Lu, Bo
磷脂酰肌醇3-激酶/Akt途径在肿瘤发生中发挥着关键作用，通过失去PTEN抑制而导致该途径失调是侵袭性前列腺癌中特别常见的现象。哺乳动物雷帕霉素靶蛋白（mTOR）是该途径中的下游信号激酶，通过激活参与蛋白质合成的因子对细胞施加促存活影响。mTOR抑制剂雷帕霉素及其衍生物对许多细胞系具有细胞毒性。最近，mTOR抑制也已显示在体外对内皮细胞和乳腺癌细胞放射增敏。由于放射是治疗前列腺癌的重要方式，我们测试了mTOR抑制剂RAD 001（依维莫司）增强放射对两种前列腺癌细胞系PC-3和DU 145的细胞毒性作用的能力。我们发现这两种细胞系在用RAD 001处理后变得更容易受到辐射，其中PTEN缺陷的PC-3细胞系显示出更大的敏感性。这种对辐射敏感性的增加与自噬的诱导有关。此外，我们发现，在这些细胞系中，用半胱天冬酶抑制剂和Bax/巴克小干扰RNA阻断凋亡增强了辐射诱导的死亡率并诱导自噬。总之，这些数据突出了mTOR作为治疗干预的分子靶点的重要性，并支持细胞死亡的非凋亡模式可能在改善肿瘤细胞杀伤中起关键作用的观点。
The phosphatidylinositol 3-kinase/Akt pathway plays a critical role in oncogenesis, and dysregulation of this pathway through loss of PTEN suppression is a particularly common phenomenon in aggressive prostate cancers. The mammalian target of rapamycin (mTOR) is a downstream signaling kinase in this pathway, exerting prosurvival influence on cells through the activation of factors involved in protein synthesis. The mTOR inhibitor rapamycin and its derivatives are cytotoxic to a number of cell lines. Recently, mTOR inhibition has also been shown to radiosensitize endothelial and breast cancer cells in vitro. Because radiation is an important modality in the treatment of prostate cancer, we tested the ability of the mTOR inhibitor RAD001 (everolimus) to enhance the cytotoxic effects of radiation on two prostate cancer cell lines, PC-3 and DU145. We found that both cell lines became more vulnerable to irradiation after treatment with RAD001, with the PTEN-deficient PC-3 cell line showing the greater sensitivity. This increased susceptibility to radiation is associated with induction of autophagy. Furthermore, we show that blocking apoptosis with caspase inhibition and Bax/Bak small interfering RNA in these cell lines enhances radiation-induced mortality and induces autophagy. Together, these data highlight the emerging importance of mTOR as a molecular target for therapeutic intervention, and lend support to the idea that nonapoptotic modes of cell death may play a crucial role in improving tumor cell kill.