Cocarcinogenic Effect of Capsaicin Involves Activation of EGFR Signaling but Not TRPV1

Department of Bioscience and Biotechnology, Konkuk University, Seoul, Korea.
Cancer Research (Impact Factor: 9.33). 09/2010; 70(17):6859-69. DOI: 10.1158/0008-5472.CAN-09-4393
Source: PubMed


Epidemiologic and animal studies revealed that capsaicin can act as a carcinogen or cocarcinogen. However, the molecular mechanisms of the cancer-promoting effects of capsaicin are not clear. Here, we report that capsaicin has a cocarcinogenic effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin carcinogenesis in vivo and is mediated through the epidermal growth factor receptor (EGFR), but not the transient receptor potential vanilloid subfamily member 1 (TRPV1). Topical application of capsaicin on the dorsal skin of 7,12-dimetylbenz(a)anthracene-initiated and TPA-promoted TRPV1 wild-type (WT) and TRPV1 knockout (KO) mice induced more and larger skin tumors in TRPV1/KO mice, suggesting a TRPV1-independent mechanism. Cyclooxygenase-2 (COX-2) was highly elevated by capsaicin treatment in tumors and murine embryonic fibroblasts from TRPV1/KO mice. Inhibitors of EGFR/MEK signaling suppressed TPA/capsaicin-induced COX-2 expression in TRPV1/KO cells, indicating that activation of EGFR and its downstream signaling is involved in COX-2 elevation. Capsaicin induced a further induction of TPA-increased COX-2 expression in EGFR/WT cells, but not in EGFR/KO cells. TPA/capsaicin cotreatment caused EGFR tyrosine phosphorylation and activated EGFR downstream signaling, including ERKs and Akt in EGFR/WT, but not EGFR/KO cells. Specific inhibition of EGFR and TRPV1 indicated that capsaicin-induced ERK activation in A431 cells was dependent on EGFR, but not TRPV1. Together, these findings suggest that capsaicin might act as a cocarcinogen in TPA-induced skin carcinogenesis through EGFR-dependent mechanisms.

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    • "The EGFR signaling pathway is associated with metastatic properties, including cell motility, adhesion, and invasion in vitro[41,42]. EGFR activates intracellular signaling cascades, including Ras/Raf/MEK/ERK and PI3K/Akt, and subsequently controls proliferation, migration, and apoptosis [43]. Activation of NF-κB and AP-1 is centrally involved in the induction of the MMP-9 gene associated with the invasion and metastasis of tumor cells by different agents, including TPA and growth factors, such as EGF [27,44,45]. "
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    • "Even if Resv induces apoptosis in cancer cells it would not compulsory lead to cancer chemoprevention, like in the case of capsaicin (8-methyl-N-vanillyl-6-nonenamide), an apoptosis inducer in a number of cancer cells, which may act as carcinogen/cocarcinogen. For example, capsaicin promoted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin carcinogenesis through activation of EGFR-dependent mechanisms [79]. "
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