TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling
TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling
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DOI：
10.1093/carcin/bgr037
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发表时间：
2011-05-01
期刊：
影响因子：
4.7
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
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作者：
Li, Shengqing;Bode, Ann M.;Dong, Zigang
除了瞬时受体电位通道香草蛋白亚家族1 （TRPV1）激动剂辣椒素外，还有两种针对该受体的拮抗剂被用作缓解疼痛的治疗药物。事实上，一些小分子TRPV1拮抗剂目前正在进行I/II期临床试验，以确定它们对缓解慢性炎症性疼痛和偏头痛的作用。然而，我们之前报道了小鼠中TRPV1的缺失会导致皮肤癌变的显著增加，这表明慢性阻断TRPV1可能会增加肿瘤发展的风险。在本研究中，我们发现一种典型的TRPV1拮抗剂AMG9810促进小鼠皮肤肿瘤的发展。局部应用AMG9810导致表皮生长因子受体（EGFR）及其下游Akt/哺乳动物雷帕霉素（mTOR）信号通路靶点的表达水平显著升高。这种增加不仅在AMG9810治疗的肿瘤组织中观察到，而且在用AMG9810治疗的皮肤组织中也发现了。在端粒酶永生化的原代人角质形成细胞中，AMG9810通过EGFR/Akt/ mtor信号通路促进增殖。综上所述，我们的数据表明TRPV1拮抗剂AMG9810通过EGFR/Akt/mTOR信号通路促进小鼠皮肤肿瘤发生。因此，应用这种化合物来缓解疼痛可能会增加患皮肤癌的风险。
In addition to capsaicin, a transient receptor potential channel vanilloid subfamily 1 (TRPV1) agonist, two kinds of antagonists against this receptor are used as therapeutic drugs for pain relief. Indeed, a number of small molecule TRPV1 antagonists are currently undergoing Phase I/II clinical trials to determine their effect on relieving chronic inflammatory pain and migraine headache pain. However, we previously reported that the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis, suggesting that chronic blockade of TRPV1 might increase the risk of tumor development. In this study, we found that a typical TRPV1 antagonist, AMG9810, promotes mouse skin tumor development. The topical application of AMG9810 resulted in a significant increase in the expression level of the epidermal growth factor receptor (EGFR) and its downstream Akt/mammalian target of rapamycin (mTOR)-signaling pathway. This increase was not only observed in AMG9810-treated tumor tissue but was also found in skin tissue treated with AMG9810. In telomerase-immortalized primary human keratinocytes, AMG9810 promoted proliferation that was mediated through the EGFR/Akt/mTOR-signaling pathway. In summary, our data suggest that the TRPV1 antagonist, AMG9810, promotes mouse skin tumorigenesis mediated through EGFR/Akt/mTOR signaling. Thus, the application of this compound for pain relief might increase the risk of skin cancer.