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
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
Blog Article
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 metabo 15-gauge finish nailer cordless 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 ashy bines protein powder management system and is specifically fitted and switched toward autophagy-mediated apoptosis directing toward a therapeutic perspective.