TY - JOUR
T1 - TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling
AU - Liy, Shengqing
AU - Bodey, Ann M.
AU - Zhuy, Feng
AU - Liu, Kangdong
AU - Zhang, Jishuai
AU - Kim, Myoung Ok
AU - Kanamata Reddy, Srinivasa Reddy
AU - Zykova, Tatiana
AU - Ma, Wei-Ya
AU - Carper, Andria L.
AU - Langfald, Alyssa K.
AU - Dong, Zigang
N1 - Funding Information:
The Hormel Foundation and National Institutes of Health (CA111356, CA111536, CA120588, R7CA081064, and ES016548).
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgr037
DO - 10.1093/carcin/bgr037
M3 - Article
C2 - 21349818
AN - SCOPUS:79955766195
SN - 0143-3334
VL - 32
SP - 779
EP - 785
JO - Carcinogenesis
JF - Carcinogenesis
IS - 5
ER -
