Curcumin suppresses AP1 transcription factor-dependent differentiation and activates apoptosis in human epidermal keratinocytes

被引:78
作者
Balasubramanian, Sivaprakasam
Eckert, Richard L.
机构
[1] Case Western Reserve Univ, Sch Med, Dept Physiol Biophys, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Dermatol, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Sch Med, Dept Reprod Biol, Cleveland, OH 44106 USA
[5] Case Western Reserve Univ, Sch Med, Dept Oncol, Cleveland, OH 44106 USA
关键词
D O I
10.1074/jbc.M606003200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The diet-derived cancer preventive agent, curcumin, inhibits skin cancer cell proliferation and tumor formation. However, its effect on normal human keratinocyte differentiation, proliferation, and apoptosis has not been adequately studied. Involucrin (hINV) is a marker of keratinocyte differentiation and a useful model for the study of chemopreventive agent action. We show that curcumin suppresses the differentiation agent-dependent activation of hINV gene expression and that an AP1 transcription factor DNA binding site in the hINV gene is required for this regulation. A protein kinase C, Ras, MEKK1, MEK3 signaling cascade controls hINV expression by regulating AP1 factor level. Curcumin treatment inhibits the novel protein kinase C-, Ras-, and MEKK1-dependent activation of hINV promoter activity and reduces the differentiation agent-dependent increase in AP1 factor level and DNA binding. This reduction requires proteasome function. In addition, curcumin treatment reduces cell number, which is associated with a reduced cyclin and cdk1 levels. Curcumin treatment also suppresses the Bcl-xL level, leading to reduced mitochondrial membrane potential and increased cleavage of procaspases and poly(ADP-ribose) polymerase. These studies provide important insights regarding the mechanism whereby curcumin acts as a chemopreventive agent in normal human epidermis.
引用
收藏
页码:6707 / 6715
页数:9
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