Effect of dimethoxycurcumin beyond degradation of androgen receptor

Abstract

Androgen receptor (AR) plays an important role in the pathogenesis of prostate cancer and acne. Dimethoxycurcumin is a newly found enhancer of AR degradation, which highlights its potential for treatment of AR-related disorders. Follicular hyperkeratosis is one essential factor in the complicated pathogenesis of acne, in which some dermatopathologists have observed overexpressed psoriasin, an activator protein (AP)-1-targeted gene product. We used the HaCaT cell line to determine the effect of dimethoxycurcumin on expression of AP-1 subunits and AP-1-targeted genes, psoriasin and cyclin D1, by luciferase reporter assay, western blotting and reverse transcriptase polymerase chain reaction. We also used flow cytometry to analyze changes in cell populations in response to increasing dose of dimethoxycurcumin. Dimethoxycurcumin inhibits psoriasin promoter activities at the basal or enhanced level induced by exogenous c-Jun/c-Fos heterodimeric AP-1. Expression of endogenous c-Jun and c-Fos, two important subunits of dimeric AP-1, was downregulated at the mRNA or protein level by dimethoxycurcumin in HaCaT cells. Inhibition of endogenous cyclin D1 occurred at both the transcript and protein levels. A shift of subpopulations of cells into sub-G1 phase was consistent with reduced cyclin D1, corresponding to dimethoxycurcumin treatment. Identification of AP-1 transcription factor as a specific target for dimethoxycurcumin-downregulated molecules in human keratinocytes suggests that this novel chemical modulates various AP-1–related events in the epidermis, including cell-cycle progression and its role as an inflammatory reservoir. We provided evidence for this because expression of cyclin D1 and psoriasin, two AP-1-regulated gene products, was inhibited by dimethoxycurcumin in HaCaT and HeLa cells. Cyclin D1 is an important cell-cycle regulator, whereas psoriasin is a potent cytokine for innate immunity. We anticipate that more diseases will benefit from this curcumin analog in the near future.