Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1

Mun Kyung Hwang, Ann M. Bode, Sanguine Byun, Nu Ry Song, Hyong Joo Lee, Ki Won Lee, Zigang Dong

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Abstract

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.

Original languageEnglish
Pages (from-to)6859-6869
Number of pages11
JournalCancer Research
Volume70
Issue number17
DOIs
Publication statusPublished - 2010 Sep 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Hwang, M. K., Bode, A. M., Byun, S., Song, N. R., Joo Lee, H., Lee, K. W., & Dong, Z. (2010). Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1. Cancer Research, 70(17), 6859-6869. https://doi.org/10.1158/0008-5472.CAN-09-4393