Curcuminoids activate p38 MAP kinases and promote UVB‐dependent signalling in keratinocytes

Abstract

Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signaling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on MAP kinase signaling in keratinoctyes were determined. Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target. These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.

Ras/ERK signaling pathway is involved in curcumin-induced cell cycle arrest and apoptosis in human gastric carcinoma AGS cells

“…Curcumin, the bioactive component extracted from turmeric rhizome of C. longa Linn, has been reported to exhibit various biological effects including anti- [10,11]. The cell cycle is mediated by the activation of cyclindependent kinases.…”

Polypodium leucotomos decreases UV‐induced epidermal cell proliferation and enhances p53 expression and plasma antioxidant capacity in hairless mice

“…p53 decreases oxidative damage to the DNA, which also contributes to its antitumor activity (16) and promotes the clearance of oxidative photoproducts, particularly cyclobutane pyrimidine dimers (CPDs), which are the main mutagens implicated in skin cancer (17). PL enhanced both p53 expression and activation in irradiated Xpc +/À mice (10), and curcuminoids also promote phosphorylation of p53 in cultured human keratinocytes through the p38 MAP kinase pathway (18). PL also decreased UVR-induced cell proliferation; this is in agreement with the observed increase in p53 expression and reinforces the anti-carcinogenic properties of PL.…”

Curcumin Differs from Tetrahydrocurcumin for Molecular Targets, Signaling Pathways and Cellular Responses

“…Curcumin was found to suppress the growth of human keratinocytes by suppression of p44/p42 MAPK activation, enhanced activation of p38 MAPK, and p53 phosphorylation; these effects were reversed by N-acetylcysteine [51]. THC, in comparison, was much less active than native curcumin in suppressing human keratinocyte growth.…”

“…•THC activated p53 and p21 more effectively than curcumin [51]. DMH, 1, 2-dimethylhydrazine; ACF, aberrant crypt foci; LDL, low-density lipoprotein; COX2, cyclooxygenage-2; THC, tetrahydrocurcumin; JNK, c-Jun N-terminal kinases; TBARS, thiobarbituric acid reactive substances; CCl4, carbon tetrachloride…”