The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis.
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SCOPE: Mechanisms involving the curcuminoids effects in decreasing the prooncogenic specificity protein (Sp) transcription factors, and Sp-regulated genes in SW-480 colon cancer cells and how the multidrug resistance protein (MDR1) inhibition is mediated by Sp suppression. METHODS AND RESULTS: HT-29 and SW-480 colon cancer and normal CCD-18Co colon fibroblast cells were treated with curcuminoids previously analyzed by HPLC. Gene and protein expression regulation were assessed by RT-PCR, transfections with expression constructs, and Western blots. Curcuminoids (2.5-10g/mL) suppressed preferentially the growth of SW-480 and HT-29 compared to CCD-18Co cells and enhanced the anticancer activity of the chemotherapeutic drug 5-fluorouracil due to the suppression of MDR1. Additionally, Sp1, Sp3, and Sp4 and Sp-regulated genes were downregulated by curcuminoids in SW-480 and this was accompanied by suppression of microRNA-27a (miR-27a) and induction of ZBTB10, an mRNA target of miR-27a and a transcriptional repressor of Sp expression. This mechanism was mediated by the induction of ROS. RNA-interference and transfection with ZBTB10-expression plasmid demonstrated that MDR1 was regulated by Sp1 and Sp3 and the disruption of the miR-27a-ZBTB10-Sp axis. CONCLUSION: Colon cancer treatment with curcuminoids will enhance the therapeutic effects of drugs in patients who have developed drug resistance.
