作为病毒性癌症进化的一部分，KSHV感染的人体内皮细胞通过上调mTORC1信号传导展现出独特的转录程序。这个事件使它们对mTOR抑制剂敏感。主要转录调节因子PTEN充当mTOR的主要调节因子，确定mTOR抑制药物的耐药性和敏感性。PTEN在KSHV相关细胞系和感染组织中经过翻译后修饰。我们目前的研究尝试理解上游调节因子PTEN在决定体外应激响应模型中KSHV感染细胞对mTOR抑制剂敏感性的功能角色。我们的分析显示，尽管发生了磷酸化，与正常和非感染细胞相比，不同KSHV感染细胞中的内源性PTEN完整水平相当高。完整PTEN的遗传过表达显示该基因在感染细胞中的功能完整性，通过细胞周期调节和线粒体介导的凋亡诱导了同步细胞死亡过程。PTEN过表达增强了mTOR抑制剂的活性，而其沉默则妨碍了针对KSHV感染细胞的这一过程。此外，我们还表明内源性PTEN在KSHV感染细胞内起到应激平衡分子的作用，并能在mTOR抑制剂处理后诱导应激敏感的死亡程序，该程序在ATM-chk2-p53轴上排列。此外，从我们的研究中发现，自噬调节是mTOR抑制剂诱导PTEN介导死亡轴的主要调节因子。当前工作临界地交叉了PTEN介导的应激平衡机制，其中自噬被用作KSHV应激管理系统的一部分，并特别适用于自噬介导的凋亡，朝向治疗前景。Copyright © 2023 Das, Pal, Das, Chakraborty, Chatterjee, Mal and Choudhuri.

As a part of viral cancer evolution, KSHV-infected human endothelial cells exert a unique transcriptional program via upregulated mTORC1 signaling. This event makes them sensitive to mTOR inhibitors. Master transcriptional regulator PTEN acts as the prime regulator of mTOR and determining factor for mTOR inhibitory drug resistance and sensitivity. PTEN is post-translationally modified in KSHV-associated cell lines and infected tissues. Our current study is an attempt to understand the functional role of upstream modulator PTEN in determining the sensitivity of mTOR inhibitors against KSHV-infected cells in an in vitro stress-responsive model. Our analysis shows that, despite phosphorylation, endogenous levels of intact PTEN in different KSHV-infected cells compared to normal and non-infected cells are quite high. Genetic overexpression of intact PTEN showed functional integrity of this gene in the infected cells in terms of induction of a synchronized cell death process via cell cycle regulation and mitochondria-mediated apoptosis. PTEN overexpression enhanced the mTOR inhibitory drug activity, the silencing of which hampers the process against KSHV-infected cells. Additionally, we have shown that endogenous PTEN acts as a stress balancer molecule inside KSHV-infected cells and can induce stress-sensitized death program post mTOR inhibitor treatment, lined up in the ATM-chk2-p53 axis. Moreover, autophagic regulation was found as a major regulator in mTOR inhibitor-induced PTEN-mediated death axis from our study. The current work critically intersected the PTEN-mediated stress balancing mechanism where autophagy has been utilized as a part of the KSHV stress management system and is specifically fitted and switched toward autophagy-mediated apoptosis directing toward a therapeutic perspective.Copyright © 2023 Das, Pal, Das, Chakraborty, Chatterjee, Mal and Choudhuri.