title: Difluorinated-curcumin (CDF) restores PTEN expression in colon cancer cells by down-regulating miR-21.
abstract: Despite recent advancement in medicine, nearly 50% of patients with colorectal cancer show recurrence of the disease. Although the reasons for the high relapse are not fully understood, the presence of chemo- and radiotherapy-resistant cancer stem/stem-like cells, where many oncomirs like microRNA-21 (miR-21) are upregulated, could be one of the underlying causes. miR-21 regulates the processes of invasion and metastasis by downregulating multiple tumor/metastatic suppressor genes including PTEN (phosphatase and tensin homolog). Tumor suppressor protein PTEN controls self-renewal of stem cells. Indeed, our current data demonstrate a marked downregulation of PTEN in SCID mice xenografts of miR-21 over-expressing colon cancer HCT116 cells. Colonospheres that are highly enriched in cancer stem/stem like cells reveal increased miR-21 expression and decreased PTEN. Difluorinated curcumin (CDF), a novel analog of the dietary ingredient curcumin, which has been shown to inhibit the growth of 5-Flurouracil + Oxaliplatin resistant colon cancer cells, downregulated miR-21 in chemo-resistant colon cancer HCT116 and HT-29 cells and restored PTEN levels with subsequent reduction in Akt phosphorylation. Similar results were also observed in metastatic colon cancer SW620 cells. Since PTEN-Akt confers drug resistance to different malignancies including colorectal cancer, our observation of normalization of miR-21-PTEN-Akt pathway by CDF suggests that the compound could be a potential therapeutic agent for chemotherapy-resistant colorectal cancer.
authors.affiliation: Department of Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Sanchita
authors.initials: S
authors.lastname: Roy
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Yu
authors.forename: Subhash B
authors.initials: SB
authors.lastname: Padhye
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Adhip P N
authors.initials: AP
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use*; D005466:Fluorocarbons / Q000494:pharmacology* / Q000627:therapeutic use*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D005466:Fluorocarbons; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D003474:Curcumin
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