A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer.
A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer.
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内质网应激和 c-Myc 降解介导的抗神经激肽-1 受体药物治疗结直肠癌的新机制
DOI：
10.1002/advs.202101936
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Fu C
中科院分区：
文献类型：
--
作者：
Shi Y;Wang X;Meng Y;Ma J;Zhang Q;Shao G;Wang L;Cheng X;Hong X;Wang Y;Yan Z;Cao Y;Kang J;Fu C
神经激肽-1受体（NK-1 R）拮抗剂被批准用于治疗癌症患者化疗相关的恶心和呕吐。物质P-NK-1 R系统在肿瘤发生中的新作用增加了将耐受性良好的NK-1 R拮抗剂重新用于癌症治疗的可能性。这项研究报告了NK-1 R高表达的人结直肠癌（CRC）患者的生存率较差，NK-1 R拮抗剂SR 140333和阿瑞匹坦诱导CRC细胞凋亡并抑制CRC异种移植物生长。NK-1 R拮抗剂治疗诱导的细胞毒性通过诱导内质网（ER）应激介导。ER应激触发钙释放，导致促生存细胞外信号调节激酶（ERK）-c-Myc信号转导的抑制。沿着ER钙释放，一条由蛋白激酶RNA样ER激酶（PERK）介导的ER应激途径被特异性激活，导致促凋亡C/EBP同源蛋白（CHOP）表达增加。此外，NK-1 R拮抗剂通过在体外和体内诱导持续的ER应激和随后的ERK-c-Myc信号转导抑制，增加CRC细胞对5-氟尿嘧啶的敏感性并克服其耐药性，从而增强化疗的疗效。总的来说，这些发现为NK-1 R拮抗剂作为单一药物或与化疗联合用于癌症治疗的疗效提供了新的机制见解。神经激肽-1受体拮抗剂通过激活内质网应激诱导细胞凋亡，被重新用作结直肠癌患者的新治疗选择。
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. The neurokinin‐1 receptor antagonists are repurposed as a new treatment option for patients with colorectal cancer via activation of endoplasmic reticulum stress to induce apoptosis.
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影响因子：
3.8
作者：
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DOI：
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影响因子：
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
Nature reviews. Cancer
影响因子：
--
作者：
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通讯作者：
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