Rapamycin promotes autophagy cell death of Kaposi's sarcoma cells through P75NTR activation
Rapamycin promotes autophagy cell death of Kaposi's sarcoma cells through P75NTR activation
复制标题
DOI：
10.1111/exd.14438
复制
发表时间：
2021-08-14
影响因子：
3.6
通讯作者：
Bonofiglio, Renzo
中科院分区：
文献类型：
--
作者：
Lupinacci, Simona;Perri, Anna;Bonofiglio, Renzo
雷帕霉素是一种广泛用于肾移植的药物，通过多种生物学相互作用发挥重要的抗癌作用，特别是在卡波西肉瘤（KS）中。在这项体内和体外研究中，我们探讨了通过神经生长因子低亲和力受体p75（NTR）激活自噬途径是否可能在雷帕霉素在S.我们的K免疫组化结果显示KS病变中自噬通路显著过度活化。KS细胞系的体外实验表明，雷帕霉素暴露通过增加自噬过程降低细胞活力，在细胞凋亡的情况下，通过转录激活p75（NTR）通过EGR 1。有趣的是，p75（NTR）基因沉默阻止了自噬过程的增加和细胞活力的降低。此外，p75（NTR）激活促进了磷酸酶和张力蛋白同源物（PTEN）的上调，这是一种调节PI 3 K/Akt/mTOR通路的肿瘤抑制因子。总之，我们的体外数据首次证明，在卡波西肉瘤中，雷帕霉素通过p75（NTR）触发的自噬是mTOR抑制剂诱导肿瘤消退的主要机制。此外，它表明，p75（NTR）蛋白分析可以作为一种新的潜在的生物标志物，预测肾移植受者受卡波西肉瘤影响的雷帕霉素的反应。
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(NTR), may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry 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(NTR) via EGR1. Interestingly, p75(NTR) gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75(NTR) activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour 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(NTR) represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75(NTR) protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma.