Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial cell (VEC) apoptosis and autophagy play an important role in the maintenance of vascular homeostasis. However, the association of molecular mechanisms between vascular endothelial cell apoptosis and autophagy has not been clarified. Here, we identified a novel triazole derivative, JL014, which could inhibit human umbilical vein vascular endothelial cell (HUVEC) apoptosis induced by deprivation of serum and fibroblast growth factor 2 and maintain HUVEC survival by promoting autophagy. Importantly, JL014 increased the mRNA and protein level of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) in HUVECs. In addition, knockdown of hnRNP E1 by RNA interference inhibited the effects of JL014 on VEC apoptosis and autophagy. Furthermore, we investigated the effect of JL014 on the expression of HMBOX1, a key VEC apoptosis inhibitor and autophagy inducer by inhibiting mTOR signaling and the level of cleaved caspase-3. Our results demonstrated that JL014 enhanced mRNA transcription and increased protein synthesis of HMBOX1. JL014 also inhibited mTOR signaling and the cleaved caspase-3 level. Mechanistic studies revealed that hnRNP E1 could bind to the promoter and 5'UTR of HMBOX1 and active HMBOX1 expression. Therefore, our results firmly establish hnRNP E1 as a new regulator of VEC apoptosis and autophagy through mediating HMBOX1 expression, and opened the door to a novel therapeutic drug for related vascular diseases.
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PMID:Novel Role of Heterogeneous Nuclear Ribonucleoprotein E1 in Regulation of Apoptosis and Autophagy by a Triazole Derivative in Vascular Endothelial Cells. 3122 88

Extracellular vesicles (EVs) have received increasing attention for their role as possible regulators of cancer. miR-221-3p is a microRNA (miR) up-regulated in EVs secreted by drug-resistant A549-GR lung cancer cells. However, the underlying mechanism through which miR-221-3p-containing EVs regulate the progression of lung cancer remains elusive. Here, we attempted to reveal the mechanism by which miR-221-3p-containing EVs secreted by drug-resistant lung cancer cells regulate the functions of surrounding cells during the progression of lung cancer. A gemcitabine-sensitive lung cancer cell line was treated with isolated drug-resistant lung cancer EVs followed by an evaluation of the proliferation and migration of sensitive lung cancer cell lines and their resistance to gemcitabine treatment. Moreover, the miR-221-3p target gene HMBOX1 was identified by the Targetscan database while the progression of lung cancer was detected by knocking down miR-221-3p or overexpressing HMBOX1, or by treating sensitive cell lines with Akt/mTOR activator and inhibitor, respectively. Furthermore, an in vivo study was performed to validate the relationship between miR-221-3p and HMBOX1 and their roles in the progression of lung cancer. The proliferation and migration of sensitive lung cancer cell lines and their resistance to drugs were significantly enhanced after the treatment with drug-resistant EVs. Knockdown of miR-221-3p (in the EV of drug-resistant lung cancer or overexpression of HMBOX1 in sensitive lung cancer cell lines) reduced the transformation of sensitive lung cell lines, whereas, the treatment of sensitive lung cell lines with Akt/mTOR activator or inhibitor significantly affected the progression of lung cancer. In vivo experiments further confirmed that miR-221-3p released by drug-resistant lung cancer cells targeted the HMBOX1 to regulate the Akt/mTOR signaling pathway and affected the progression of lung cancer. We conclude that miR-221-3p-containing EVs secreted by drug-resistant lung cancer cells can potentially activate the Akt/mTOR signaling pathway by inhibiting HMBOX1, promoting the progression of lung cancer. The regulation of miR-221-3p represents a novel therapeutic target for the treatment of lung cancer.
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PMID:Extracellular vesicle-associated microRNA-221-3p secreted by drug-resistant lung cancer cells targets HMBOX1 to promote the progression of lung cancer. 3321 94