哺乳动物雷帕霉素标靶（ mTOR ）是一种对细胞生长和增殖至关重要的蛋白激酶。 mTOR 是作为 2 种独特的多蛋白复合物的一部分来发挥作用的。这 2 种复合物是 mTOR 复合物 -1 （ mTORC1 ）及 mTOR 复合物 -2 （ mTORC2 ），它们都参与 AKT 信号级联放大反应（这是一种据报道在许多人类癌症中都高度活跃的通路）。 丧失肿瘤抑制子 PTEN 会通过 AKT 而高度激活 mTOR ，这是人类前列腺癌症中最常见的事件之一。
在2009年1月27日刊《科学》杂志的一篇 Research Article 中， Nardella 等人研究显示，对 mTOR 的活性（可通过这 2 种复合物来消除信号通路）进行有条件地灭活对成年小鼠的前列腺影响甚小，但却能抑制前列腺的与 PTEN 的丧失所相关的肿瘤发生。这些发现因而支持这样一个基本原理，即研发以 mTORC1 和 mTORC2 为标靶的特殊 mTOR 抑制剂可治疗由于 PTEN 缺乏和异常 mTOR 信号而引发的肿瘤。 （生物谷Bioon.com）
生物谷推荐原始出处：
Sci. Signal., 27 January 2009 DOI: 10.1126/scisignal.2000189
Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis
Caterina Nardella1, Arkaitz Carracedo1*, Andrea Alimonti1*, Robin M. Hobbs1, John G. Clohessy1, Zhenbang Chen1, Ainara Egia1, Alessandro Fornari2,3, Michelangelo Fiorentino2, Massimo Loda2,4, Sara C. Kozma5, George Thomas5, Carlos Cordon-Cardo6, and Pier Paolo Pandolfi1
1 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Department of Biomedical Sciences and Human Oncology, Molinette Hospital, University of Turin, 10126 Turin, Italy.
4 Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
5 Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
6 Department of Pathology, Columbia University, New York, NY 10032, USA.
Abstract: The mammalian target of rapamycin (mTOR) is a crucial effector in a complex signaling network commonly disrupted in cancer. mTOR exerts its multiple functions in the context of two different multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Loss of the tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) can hyperactivate mTOR through AKT and represents one of the most frequent events in human prostate cancer. We show here that conditional inactivation of mTor in the adult mouse prostate is seemingly inconsequential for this postmitotic tissue. Conversely, inactivation of mTor leads to a marked suppression of Pten loss–induced tumor initiation and progression in the prostate. This suppression is more pronounced than that elicited by the sole pharmacological abrogation of mTORC1. Acute inactivation of mTor in vitro also highlights the differential requirement of mTor function in proliferating and transformed cells. Collectively, our data constitute a strong rationale for developing specific mTOR inhibitors targeting both mTORC1 and mTORC2 for the treatment of tumors triggered by PTEN deficiency and aberrant mTOR signaling.
