Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer

西妥昔单抗 癌变 结直肠癌 癌症研究 吗啡 医学 癌症 信号转导 内科学 化学 生物 细胞生物学
作者
Hong Lu,Hao Zhang,Meilin Weng,Jin Zhang,Nan Jiang,Juan P. Cata,Duan Ma,Wan‐Kun Chen,Changhong Miao
出处
期刊:Journal of Cellular Physiology [Wiley]
卷期号:236 (6): 4445-4454 被引量:32
标识
DOI:10.1002/jcp.30161
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 transactivation 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.
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