Garg Rachana, Ramchandani Asha G, Maru Girish B
Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410 208, India.
Carcinogenesis. 2008 Jun;29(6):1249-57. doi: 10.1093/carcin/bgn114. Epub 2008 May 13.
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 mumol) alone did not alter the basal activity/levels, its pre-treatment decreased the TPA-induced translocation of PKC isozymes (alpha, beta, gamma, epsilon, eta), 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.
姜黄素已被证明可抑制12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）诱导的小鼠皮肤肿瘤促进作用以及一些TPA反应性标志物。然而，其作用机制尚未完全阐明。本研究着重于了解TPA的主要细胞受体蛋白激酶C（PKC）在介导TPA诱导的小鼠皮肤生物学反应中的作用，随后阐明姜黄素对PKC及其下游靶分子的影响。与对照组相比，单次局部应用TPA（5 nmol）于皮肤可增加PKC从胞质向颗粒部分的转位，这是根据活性和蛋白质水平来确定的。局部单独应用或在TPA之前应用Ro - 31 - 8220（PKC抑制剂，1 nmol）可抑制两个区室中的PKC活性，但不影响TPA诱导的蛋白质转位。相反，尽管姜黄素（10 μmol）单独使用不会改变基础活性/水平，但其预处理可降低TPA诱导的PKC同工酶（α、β、γ、ε、η）的转位，从而导致活性发生相应改变。尽管Ro - 31 - 8220（活性抑制）和姜黄素（减少转位）在调节PKC方面作用方式不同，但它们的预处理可减弱TPA诱导的丝裂原活化蛋白激酶和转录因子（c - jun、c - fos和核因子 - κB）以及与细胞增殖（细胞周期蛋白D1和鸟氨酸脱羧酶）、细胞死亡（Bax和Bcl2）、炎症（环氧化酶 - 2和前列腺素E2）和氧化应激（8 - 羟基 - 2'-脱氧鸟苷）相关的下游靶蛋白在皮肤中的水平。这些结果证明了PKC在TPA介导的皮肤细胞反应中的关键作用，并且姜黄素通过PKC调节跨膜信号转导，以影响TPA诱导的小鼠皮肤生化和分子改变。
