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Advanced Science

IF: 14.3
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A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer

Published:3 October 2021 DOI: 10.1002/advs.202101936 PMID: 34605226
Yue Shi, Xi Wang, Yueming Meng, Junjie Ma, Qiyu Zhang, Gang Shao, Lingfei Wang, Xurui Cheng, Xiangyu Hong, Yong Wang, Zhibin Yan, Yihai Cao, Jian Kang, Caiyun Fu

Abstract

The neurokinin-1 receptor (NK-1R) antagonists are approved as treatment for chemotherapy-associated nausea and vomiting in cancer patients. The emerging role of the substance P-NK-1R system in oncogenesis raises the possibility of repurposing well-tolerated NK-1R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK-1R expression have poor survival, and NK-1R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK-1R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal-regulated kinase (ERK)-c-Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA-like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C/EBP-homologous protein (CHOP). Moreover, NK-1R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5-fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK-c-Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK-1R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
U0126 109511-58-2 C18H16N6S2 151 suppliers $44.00-$1950.00
U0126 109511-58-2 C18H16N6S2 151 suppliers $44.00-$1950.00
U0126 109511-58-2 C18H16N6S2 151 suppliers $44.00-$1950.00
U0126 109511-58-2 C18H16N6S2 151 suppliers $44.00-$1950.00

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