Inhibition of Mycobacterial Infection by the Tumor Suppressor PTEN
Inhibition of Mycobacterial Infection by the Tumor Suppressor PTEN
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DOI：
10.1074/jbc.m112.351940
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发表时间：
2012-06-29
影响因子：
4.8
通讯作者：
Jiang, Xuejun
中科院分区：
文献类型：
--
作者：
Huang, Guochang;Redelman-Sidi, Gil;Jiang, Xuejun
肿瘤抑制因子PTEN是一种脂质磷酸酶，在各种人类癌症中经常发生突变。PTEN抑制肿瘤细胞增殖、存活和生长主要通过抑制PI 3 K-Akt信号通路，该通路通过磷脂酰肌醇3，4，5-三磷酸的去磷酸化。除了在肿瘤抑制中的作用之外，PTEN-PI 3 K途径还控制许多细胞功能，其中一些可能对细胞抵抗感染很重要。目前，致瘤信号通路和细胞对感染的易感性之间的交叉点还没有很好的定义。在这项研究中，我们报告说，PTEN信号调节感染的非癌细胞和癌细胞的多种细胞内分枝杆菌病原体和药理学调制的PTEN信号可以影响分枝杆菌感染。我们发现，PTEN缺陷使多种类型的细胞对支原体和牛分枝杆菌卡介苗（BCG）感染高度敏感。PTEN的脂质磷酸酶活性是减弱感染所必需的。此外，我们发现分枝杆菌感染激活宿主细胞Akt磷酸化，并且Akt或PI 3 K活性的药理学抑制降低了细胞内感染的水平。有趣的是，抑制mTOR（Akt信号传导的下游组分之一和有希望的癌症治疗靶点）也降低了乳腺上皮癌MCF-7细胞中的细胞内卡介苗水平。这些发现证明了PTEN调控的途径在病原体感染中的关键作用。PTEN-PI 3 K-Akt mTOR状态与分枝杆菌感染易感性的关系表明，分枝杆菌病原体与癌细胞的相互作用可能受到肿瘤细胞中遗传改变的影响。
The tumor suppressor PTEN is a lipid phosphatase that is frequently mutated in various human cancers. PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. In addition to it role in tumor suppression, the PTEN-PI3K pathway controls many cellular functions, some of which may be important for cellular resistance to infection. Currently, the intersection between tumorigenic signaling pathways and cellular susceptibility to infection is not well defined. In this study we report that PTEN signaling regulates infection of both noncancerous and cancerous cells by multiple intracellular mycobacterial pathogens and that pharmacological modulation of PTEN signaling can affect mycobacterial infection. We found that PTEN deficiency renders multiple types of cells hyper-susceptible to infection by Mycoplasma and Mycobacterium bovis Bacillus Calmette-Guerin ( BCG). The lipid phosphatase activity of PTEN is required for attenuating infection. Furthermore, we found mycobacterial infection activates host cell Akt phosphorylation, and pharmacological inhibition of Akt or PI3K activity reduced levels of intracellular infection. Intriguingly, inhibition of mTOR, one of the downstream components of the Akt signaling and a promising cancer therapeutic target, also lowered intracellular Bacillus Calmette-Guerin levels in mammary epithelial cancer MCF-7cells. These findings demonstrate a critical role of PTEN-regulated pathways in pathogen infection. The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells.