mTOR Inhibition Role in Cellular Mechanisms

Abstract

The mammalian target of rapamycin inhibitors (mTOR-I), drugs widely used in transplant medicine and oncology, exert their function by inhibiting a serine/threonine kinase with a pivotal role in cellular metabolism and in a wide range of eukaryotic biological/cellular functions and signaling networks. Additionally, as largely described, the inhibition of mTOR has a major impact on cellular metabolism by stimulating synthesis of proteins and lipids, inhibiting catabolic processes, such as lysosome biogenesis and autophagy, and controlling cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis. All these biological functions are essential to guarantee body homeostasis and survival. Therefore, it is necessary for clinicians and researchers to better understand this complex pathway to ameliorate patients' treatment empathizing therapeutic effects to minimize/avoid toxicities and to propose new valuable research strategies.The aim of this article has been to underline the complexity of the mTOR pathway and to review the recent literature describing the consequences of its inhibition on several cellular functions including (a) protein synthesis, (b) cell cycle,

Regulatory B cells and advances in transplantation

“…CNIs and mTOR inhibitors are known to exert immunosuppression mainly by inhibiting T cell proliferation and their effects on B cells have not been extensively studied . Lower numbers of IL‐10‐producing B cells and CD19 + CD24 hi CD38 hi transitional B cells are detected in CNI‐ and mTOR inhibitor‐treated patients than in untreated healthy individuals.…”

“…However, only mTOR inhibitor‐treated patients rather than CNI‐treated patients exhibit expanded CD4 + CD25 + FOXP3 + Tregs, implying that an increase in Tregs compensates for a reduction in Bregs . The compensation mechanism probably explains the clinical observation that conversion to mTOR inhibition increases Treg numbers and then improves renal function after CNI discontinuation in renal transplantation patients …”

“…[122][123][124] CNIs and mTOR inhibitors are known to exert immunosuppression mainly by inhibiting T cell proliferation and their effects on B cells have not been extensively studied. 122,123,125 Lower numbers of IL-10-producing B cells and CD19 + CD24 hi CD38 hi transitional B cells are detected in CNI-and mTOR inhibitor-treated patients than in untreated healthy individuals. However, only mTOR inhibitortreated patients rather than CNI-treated patients exhibit expanded CD4 + CD25 + FOXP3 + Tregs, implying that an increase in Tregs compensates for a reduction in Bregs.…”

“…126 The compensation mechanism probably explains the clinical observation that conversion to mTOR inhibition increases Treg numbers and then improves renal function after CNI discontinuation in renal transplantation patients. 124,125…”

Liver transplantation for hepatocellular carcinoma - non-cancer factors and implications for improving outcome beyond standard tumor criteria

“…The use of mammalian target of rapamycine inhibitors (mTORis), such as rapamycine (SRL) and everolimus (EVL) provide anti-cancer effects by inhibiting the PI3K/AKt/mTOR pathway beyond its immunosuppressive capabilities [143,144] . Therefore, many hopes had been placed in this immunosuppressant in recent years for reducing the risk of post-LT HCC recurrence without affecting the immunological outcome [145][146][147][148] .…”