title: Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer.
abstract: Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial-mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC.
authors: Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: Shusuke
authors: S
authors: Toden
authors: Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: Yoshinaga
authors: Y
authors: Okugawa
authors: Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: Thomas
authors: T
authors: Jascur
authors: Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and.
authors: Dominik
authors: D
authors: Wodarz
authors: Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and.
authors: Natalia L
authors: NL
authors: Komarova
authors: Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: Constanze
authors: C
authors: Buhrmann
authors: Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: Mehdi
authors: M
authors: Shakibaei
authors: Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany.
authors: C Richard
authors: CR
authors: Boland
authors: Center for Gastrointestinal Research, and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA, Department of Ecology and Evolution and Department of Mathematics, University of California, Irvine, CA, USA and Institute of Anatomy, Ludwig-Maximilian University, Munich, Germany ajay.goel@baylorhealth.edu.
authors: Ajay
authors: A
authors: Goel
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D003474:Curcumin; D005472:Fluorouracil
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