The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi’s Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study we explored whether the activation of the autophagic pathway through the low-affinity receptor for Nerve Growth Factor, p75 , may have a pivotal role in the anti-cancer effect exerted by Rapamycin in KS. Our immunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75 via EGR1. Interestingly, p75 gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75 activation promoted the upregulation of Phosphatase and Tensin Homolog (PTEN), a tumor suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi’s sarcoma, autophagy triggered by Rapamycin through p75 represented a major mechanism by which mTOR inhibitors may induce tumor regression. Additionally, it suggested that p75 protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi’s sarcoma.This article is protected by copyright. All rights reserved.
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Antonella La Russa