AUTHOR=Das Piyanki , Pal Sonali , Das Nilanjana , Chakraborty Koushik , Chatterjee Koustav , Mal Sudipa , Choudhuri Tathagata 

TITLE=Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1062462

DOI=10.3389/fmolb.2023.1062462

ISSN=2296-889X

ABSTRACT=As a part of viral cancer evolution,   KSHV-infected human endothelial cells exert an unique transcriptional program via up-regulated 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 tissue.Our current study is an attempt of understanding the functional role of  upstream modulator PTEN as  determining the sensitivity of mTOR inhibitors against KSHV-infected cells in invitro stress responsive model. Our analysis shows that, inspite of 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 synchronised cell death process via cell cycle regulation and mitochondria-mediated apoptosis. PTEN overexpression enhanced the mTOR inhibitory drug activity and 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 programme post mTOR inhibitor treatment, lined up in ATM-chk2-p53 axis. Moreover, autophagic regulation found as major regulator in mTOR inhibitor induced PTEN mediated death axis from our study. This current work critically intersected the PTEN mediated stress balancing mechanism where autophagy has been utilized as a part of KSHV stress management system, is specifically fitted and switched towards autophagy mediated apoptosis directing towards a therapeutic perspective.