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首页> 外文期刊>Journal of cellular physiology. >Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer
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Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

机译：吗啡可以促进肿瘤发生和西妥昔单抗通过激活人类表皮生长因子受体信号电阻结肠直肠癌

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摘要

Morphine, a mu-opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time-concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transac-tivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT-MTOR and RAS-MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine-EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab-resistant CRC patients.
机译：吗啡,mu-opioid受体(铁道部)受体激动剂被广泛用于治疗晚期癌症疼痛。转移,吗啡和抗癌药物同时给出。表明,吗啡可能的风险因素促进肿瘤的恶性潜能。这项研究中,我们报告治疗吗啡激活铁道部和可能导致的促进增殖、迁移和入侵HCT116 DLD1结肠直肠癌(CRC)细胞time-concentration依赖。此外,吗啡也能做出贡献西妥昔单抗耐药、靶向药物广泛用于治疗先进CRC诱导表皮生长因子受体的激活(EGFR)。增殖、迁移、入侵和药物阻力,这可能是由铁道部逆转击倒或添加nalmefene,铁道部受体拮抗剂。分析表明,吗啡选择性诱导表皮生长因子受体的transactivation。transac-tivation导致的激活ERK1/2和AKT。通过铁道部的transactivation EGFR。下游信号通路AKT-MTOR和RAS-MAPK,增加扩散、迁移和入侵,并促进抗表皮生长因子受体抑制剂CRC细胞系。验证,西妥昔单抗EGFR抑制强烈逆转的protumoral效应吗啡在体外和体内。提供证据证明morphine-EGFR信号可能是一个有前途的CRC的治疗目标病人,尤其是cetuximab-resistant CRC病人。

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