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.

Abstract

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 (2.5-10 μg/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.

• Authors: Giuliana D Noratto, Indira Jutooru, Stephen Safe, Gabriela Angel-Morales, Susanne U Mertens-Talcott
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 57 Issue 9 Pg. 1638-48 (Sep 2013) ISSN: 1613-4133 [Electronic] Germany
• PMID: 23471840 (Publication Type: Journal Article)
• Copyright: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• MIRN27 microRNA, human
• MicroRNAs
• RNA, Small Interfering
• Reactive Oxygen Species
• Repressor Proteins
• Sp Transcription Factors
• ZBTB10 protein, human
• Curcumin
• Fluorouracil

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (genetics, metabolism)
• Curcumin (pharmacology)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic
• HT29 Cells
• Humans
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Plasmids (genetics)
• RNA Interference (drug effects)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Sp Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Transfection