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: Sanchita Roy, Yingjie Yu, Subhash B Padhye, Fazlul H Sarkar, Adhip P N Majumdar
• Journal: PloS one (PLoS One) Vol. 8 Issue 7 Pg. e68543 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23894315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Fluorocarbons
• MIRN21 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Curcumin

Topics

• Animals
• Blotting, Western
• Colonic Neoplasms (drug therapy, metabolism)
• Curcumin (analogs & derivatives, pharmacology, therapeutic use)
• Fluorocarbons (pharmacology, therapeutic use)
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• Mice, SCID
• MicroRNAs (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Xenograft Model Antitumor Assays