A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer
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 trea...
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| Format: | Article |
| Language: | English |
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Wiley
2021-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202101936 |
| _version_ | 1818718756805804032 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yue Shi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T19:56:07Z |
| format | Article |
| id | doaj.art-1eb90bc6cfbb44059cfc40576f2da05f |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-17T19:56:07Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1eb90bc6cfbb44059cfc40576f2da05f2022-12-21T21:34:36ZengWileyAdvanced Science2198-38442021-11-01821n/an/a10.1002/advs.202101936A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal CancerYue Shi0Xi Wang1Yueming Meng2Junjie Ma3Qiyu Zhang4Gang Shao5Lingfei Wang6Xurui Cheng7Xiangyu Hong8Yong Wang9Zhibin Yan10Yihai Cao11Jian Kang12Caiyun Fu13Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaDepartment of Oncology No. 903 Hospital of PLA Joint Logistic Support Force Xi Hu Affiliated Hospital of Hangzhou Medical College Hangzhou 310013 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaDepartment of Oncology No. 903 Hospital of PLA Joint Logistic Support Force Xi Hu Affiliated Hospital of Hangzhou Medical College Hangzhou 310013 ChinaDepartment of Oncology No. 903 Hospital of PLA Joint Logistic Support Force Xi Hu Affiliated Hospital of Hangzhou Medical College Hangzhou 310013 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaDepartment of Microbiology Tumor and Cell Biology Karolinska Institute Stockholm 171 77 SwedenOncogenic Signalling and Growth Control Program Peter MacCallum Cancer Centre 305 Grattan Street Melbourne Victoria 3000 AustraliaZhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and Medicine Zhejiang Sci‐Tech University Hangzhou 310018 ChinaAbstract 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.https://doi.org/10.1002/advs.202101936chemotherapy resistanceER stresshuman colorectal cancerMAPK signal pathwayneurokinin‐1 receptor |
| spellingShingle | 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 A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer Advanced Science chemotherapy resistance ER stress human colorectal cancer MAPK signal pathway neurokinin‐1 receptor |
| title | A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer |
| title_full | A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer |
| title_fullStr | A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer |
| title_full_unstemmed | A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer |
| title_short | A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer |
| title_sort | novel mechanism of endoplasmic reticulum stress and c myc degradation mediated therapeutic benefits of antineurokinin 1 receptor drugs in colorectal cancer |
| topic | chemotherapy resistance ER stress human colorectal cancer MAPK signal pathway neurokinin‐1 receptor |
| url | https://doi.org/10.1002/advs.202101936 |
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