title: TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling.
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.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue North East, Austin, MN 55912, USA.
authors.forename: Shengqing
authors.initials: S
authors.lastname: Li
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Jishuai
authors.initials: J
authors.lastname: Zhang
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zykova
authors.forename: Wei-ya
authors.initials: WY
authors.lastname: Ma
authors.forename: Andria L
authors.initials: AL
authors.lastname: Carper
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Langfald
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000178:Acrylamides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D003043:Cocarcinogenesis; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002273:Carcinogens; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt