title: Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1.
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.
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Nu Ry
authors.initials: NR
authors.lastname: Song
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002211:Capsaicin / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D003043:Cocarcinogenesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004357:Drug Synergism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000172:deficiency / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D019061:src-Family Kinases; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin