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.

The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update

“…In addition, curcumin is reported to decrease cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells (Mendonca et al, 2013), increase phosphorylation of ERK1/2 and induced protein expression of tumour suppressor p53 and FOXO3a in a dose-dependent manner in nasopharyngeal carcinoma . This resulted in metastasis inhibition (Roy et al, 2013). Curcumin itself increases the expression of miR9 in a dose-dependent manner in SKOV3 ovarian cancer cells ultimately leading to apoptosis .…”

Omega-3 Fatty Acid Is a Potential Preventive Agent for Recurrent Colon Cancer

“…EGFR, which is known to be activated in CRC leads to induction of PTEN/Akt axis (35). In addition, we have reported that miR-21 mediated induction of colon CSCs is associated with down-regulation and decreased phosphorylation of PTEN (decreased activation) leading to activation of Akt (36, 37). Figure 4E demonstrates a marked increase in pPTEN and decreased pAkt levels over the corresponding controls in response to 20 µM EPA + FuOx (Fig.…”

Impact of curcumin on the regulation of microRNAs in colorectal cancer

“…A novel curcumin analog with improved stability and bioavailability, difluorinated curcumin (CDF), has been shown to reduce miR-21 expression thus increasing miR-21 target protein, phosphatase, and tensin homolog (PTEN). This effect mediates the reduction of Akt activity and suppression of growth and metastasis of colon cancer cells [23]. It was also demonstrated that repression of miR-21 expression in HCT-116 and HT-29 colon cancer cells induces differentiation.…”