Carcinogenesis Advance Access originally published online on May 13, 2008
Carcinogenesis 2008 29(6):1249-1257; doi:10.1093/carcin/bgn114
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Curcumin decreases 12-O-tetradecanoylphorbol-13-acetate-induced protein kinase C translocation to modulate downstream targets in mouse skin
Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410 208, India
* To whom correspondence should be addressed. Tel: +91 22 27405022; Fax: +91 22 27405085/+91 22 27415894; Email: gmaru{at}actrec.gov.in
Curcumin has been shown to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumour promotion and some of the TPA-responsive markers in mouse skin. However, its mechanism of action is not fully elucidated. The present study focuses on understanding the role of protein kinase C (PKC), the major cellular receptor of TPA, in mediating TPA-induced biological responses in mouse skin and subsequently, elucidating the effects of curcumin on PKC and its downstream target molecules. As compared with controls, single topical application of TPA (5 nmol) to skin increased the translocation of PKC from cytosolic to particulate fraction, determined in terms of activity and protein levels. Ro-31- 8220 (PKC inhibitor, 1 nmol) when applied topically, alone or prior to TPA, inhibited PKC activity in both the compartments but did not affect the TPA-induced protein translocation. In contrast, though curcumin (10 µmol) alone did not alter the basal activity/levels, its pre-treatment decreased the TPA-induced translocation of PKC isozymes (
, β, 
, 
, 
), resulting in appropriate alterations in activity. Despite differences in modes of action of Ro-31-8220 (activity inhibition) and curcumin (decreasing translocation) in modulating PKC, their pre-treatment blunted the TPA-induced levels of mitogen-activated protein kinases and transcription factors (c-jun, c-fos and nuclear factor-kappa B) and downstream target proteins associated with cell proliferation (cyclin D1 and ornithine decarboxylase), cell death (Bax and Bcl2), inflammation (cyclooxygenase-2 and prostaglandin E2) and oxidative stress (8-hydroxy-2'-deoxyguanosine) in skin. These results demonstrate the crucial role of PKC in TPA-mediated cellular responses in skin and that curcumin modulates transmembrane signal transduction via PKC to affect TPA-induced biochemical and molecular alterations in mouse skin.
Abbreviations: AP-1, activator protein-1; COX-2, cyclooxygenase-2; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun N-terminal protein kinase; MAPK, mitogen-activated protein kinase; NF-
B, nuclear factor-kappa B; ODC, ornithine decarboxylase; 8-OH-dG, 8-hydroxy-2'-deoxyguanosine; PGE2, prostaglandin E2; PKC, protein kinase C; p38, p38 protein kinase; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received March 14, 2008; revised April 25, 2008; accepted April 29, 2008.
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