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

• Published in: Carcinogenesis (New York) Vol. 32; no. 5; pp. 779 - 785
• Main Authors: SHENGQING LI, BODE, Ann M, LANGFALD, Alyssa K, ZIGANG DONG, FENG ZHU, KANGDONG LIU, JISHUAI ZHANG, MYOUNG OK KIM, REDDY, Kanamata, ZYKOVA, Tatyana, MA, Wei-Ya, CARPER, Andria L
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2011
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Acrylamides - administration & dosage; Acrylamides - toxicity; Animals; Biological and medical sciences; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - toxicity; Carcinogenesis; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Cell Proliferation; Cell Transformation, Neoplastic - drug effects; Cells, Cultured; Chemical agents; Cocarcinogenesis; Female; Humans; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - metabolism; Male; Medical sciences; Mice; Mice, Hairless; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; Skin Neoplasms - chemically induced; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; Tumors; Rodentia; Akt protein kinase; Tumorigenicity; Carcinogenesis; Epidermal growth factor receptor; Signal transduction; Vertebrata; VR1 vanilloid receptor; TRPV1 vanilloid receptor; Mammalia; Mouse; Animal; Skin; Antagonist
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr037

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.