哺乳動(dòng)物雷帕霉素標(biāo)靶（ mTOR ）是一種對(duì)細(xì)胞生長(zhǎng)和增殖至關(guān)重要的蛋白激酶。 mTOR 是作為 2 種獨(dú)特的多蛋白復(fù)合物的一部分來(lái)發(fā)揮作用的,。這 2 種復(fù)合物是 mTOR 復(fù)合物 -1 （ mTORC1 ）及 mTOR 復(fù)合物 -2 （ mTORC2 ）,，它們都參與 AKT 信號(hào)級(jí)聯(lián)放大反應(yīng)（這是一種據(jù)報(bào)道在許多人類癌癥中都高度活躍的通路）,。 喪失腫瘤抑制子 PTEN 會(huì)通過(guò) AKT 而高度激活 mTOR ,，這是人類前列腺癌癥中最常見的事件之一,。
在2009年1月27日刊《科學(xué)》雜志的一篇 Research Article 中,， Nardella 等人研究顯示,，對(duì) mTOR 的活性（可通過(guò)這 2 種復(fù)合物來(lái)消除信號(hào)通路）進(jìn)行有條件地滅活對(duì)成年小鼠的前列腺影響甚小,，但卻能抑制前列腺的與 PTEN 的喪失所相關(guān)的腫瘤發(fā)生。這些發(fā)現(xiàn)因而支持這樣一個(gè)基本原理,，即研發(fā)以 mTORC1 和 mTORC2 為標(biāo)靶的特殊 mTOR 抑制劑可治療由于 PTEN 缺乏和異常 mTOR 信號(hào)而引發(fā)的腫瘤,。 （生物谷Bioon.com）
生物谷推薦原始出處：
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.
