TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling

Shengqing Liy, Ann M. Bodey, Feng Zhuy, Kangdong Liu, Jishuai Zhang, Myoung Ok Kim, Srinivasa Reddy Kanamata Reddy, Tatiana Zykova, Wei-Ya Ma, Andria L. Carper, Alyssa K. Langfald, Zigang Dong

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)779-785
Number of pages7
JournalCarcinogenesis
Volume32
Issue number5
DOIs
StatePublished - May 2011

Bibliographical note

Funding Information:
The Hormel Foundation and National Institutes of Health (CA111356, CA111536, CA120588, R7CA081064, and ES016548).

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