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The emerging role of the substance P\u2010NK\u20101R system in oncogenesis raises the possibility of repurposing well\u2010tolerated NK\u20101R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK\u20101R expression have poor survival, and NK\u20101R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK\u20101R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal\u2010regulated kinase (ERK)\u2010c\u2010Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA\u2010like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C\/EBP\u2010homologous protein (CHOP). Moreover, NK\u20101R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5\u2010fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK\u2010c\u2010Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK\u20101R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.<\/jats:p>","DOI":"10.1002\/advs.202101936","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T08:33:29Z","timestamp":1633422809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["A Novel Mechanism of Endoplasmic Reticulum Stress\u2010 and c\u2010Myc\u2010Degradation\u2010Mediated Therapeutic Benefits of Antineurokinin\u20101 Receptor Drugs in Colorectal Cancer"],"prefix":"10.1002","volume":"8","author":[{"given":"Yue","family":"Shi","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci\u2010Tech University  Hangzhou 310018 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