Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs

BMC Cancer

Shruti U Gandhy⁵  KyoungHyun Kim¹  Lesley Larsen³  Rhonda J Rosengren²  Stephen Safe⁴ 

[1] Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd, Houston, TX, 77030, USA

[2] Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, 9054, New Zealand

[3] Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand

[4] Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX, 77843-4466, USA

[5] College of Medicine, Texas A&M Health Sciences Center, Houston, TX, 77030, USA

关键词: MicroRNAs;    Sp transcription factors;    ROS induction;    Curcumin;   

Others  :  1080047
DOI  :  10.1186/1471-2407-12-564

 received in 2012-04-13, accepted in 2012-11-23,  发布年份 2012

【 摘 要 】

Background

Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells.

Methods

The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression.

Results

The IC₅₀ (half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that regulate these repressors.

Conclusions

These results identify a new and highly potent curcumin derivative and demonstrate that in cells where curcumin and RL197 induce ROS, an important underlying mechanism of action involves perturbation of miR-ZBTB10/ZBTB4, resulting in the induction of these repressors which downregulate Sp transcription factors and Sp-regulated genes.

【 授权许可】

   
2012 Gandhy et al.; licensee BioMed Central Ltd.

【 图 表 】

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