期刊
ADVANCED SCIENCE
卷 8, 期 21, 页码 -出版社
WILEY
DOI: 10.1002/advs.202101936
关键词
chemotherapy resistance; ER stress; human colorectal cancer; MAPK signal pathway; neurokinin-1 receptor
资金
- National Natural Science Foundation of China [81770176, 31470071]
- Ministry of Eduction (MOE) Key Laboratory of Biosystems Homeostasis and Protec-tion (Zhejiang University) [2020BHPKF001]
- Special support plan for Zhejiang Province high-level talents [2019R52011]
The study reveals the potential efficacy of NK-1R antagonists in colorectal cancer treatment, demonstrating their ability to induce cell death, inhibit tumor growth, and enhance sensitivity to chemotherapy.
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.
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