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Difluorinated-curcumin (CDF) restores PTEN expression in colon cancer cells by down-regulating miR-21.

Roy S, Yu Y, Padhye SB, Sarkar FH, Majumdar AP - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America.

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.

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Photomicrograph of attached parental (P) and floating colonospheres (Sp) of HCT116 (A) and HT29 (B) colon cancer cells (upper panel); the middle panel represents the results of quantitative real time RT-PCR showing upregulation of miR-21 in colonospheres (Sp) when compared with the corresponding parental control (P), and western blot (lower panel) showing the relative expression of PTEN, pAKT, total Akt in parental cell and their corresponding colonospheres.
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pone-0068543-g002: Photomicrograph of attached parental (P) and floating colonospheres (Sp) of HCT116 (A) and HT29 (B) colon cancer cells (upper panel); the middle panel represents the results of quantitative real time RT-PCR showing upregulation of miR-21 in colonospheres (Sp) when compared with the corresponding parental control (P), and western blot (lower panel) showing the relative expression of PTEN, pAKT, total Akt in parental cell and their corresponding colonospheres.

Mentions: Colonospheres, considered to be surrogate tumors, are highly enriched in CSCs/CSLCs [22]. To determine whether miR-21 and its target protein PTEN are involved in regulating the functional properties of colonospheres, expressions of miR-21, PTEN and Akt, the downstream effectors of PTEN were analyzed in colonospheres generated from HCT116 and HT29. Both HCT116 and HT29 cell lines formed well-rounded spheroids (Figs. 2A & B; upper panel). Expression of miR-21, as determined by qRT-PCR, was found to be 4-5-fold higher in colonospheres, formed by both cell lines, compared to their corresponding parental cells (Figs. 2A & 2B; middle panel). On the other hand, Western-blot analysis revealed decreased expression of PTEN in colonospheres, compared to the corresponding parental cells (Figs. 2A & 2B; lower panel). As expected, reduction in PTEN in colonospheres was associated with increased activation of Akt, as demonstrated by marked increases in relative concentrations of p-Akt when compared with the corresponding parental cells (Figs. 2A & 2B lower. panel). Taken together, the results suggest that an increase in miR-21 in colonospheres that leads to reduction in PTEN activates Akt signaling pathway, which may play a role in regulating the tumorigenic properties of colonospheres that are enriched in CSCs/CSLCs.


Difluorinated-curcumin (CDF) restores PTEN expression in colon cancer cells by down-regulating miR-21.

Roy S, Yu Y, Padhye SB, Sarkar FH, Majumdar AP - PLoS ONE (2013)

Photomicrograph of attached parental (P) and floating colonospheres (Sp) of HCT116 (A) and HT29 (B) colon cancer cells (upper panel); the middle panel represents the results of quantitative real time RT-PCR showing upregulation of miR-21 in colonospheres (Sp) when compared with the corresponding parental control (P), and western blot (lower panel) showing the relative expression of PTEN, pAKT, total Akt in parental cell and their corresponding colonospheres.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3722247&req=5

pone-0068543-g002: Photomicrograph of attached parental (P) and floating colonospheres (Sp) of HCT116 (A) and HT29 (B) colon cancer cells (upper panel); the middle panel represents the results of quantitative real time RT-PCR showing upregulation of miR-21 in colonospheres (Sp) when compared with the corresponding parental control (P), and western blot (lower panel) showing the relative expression of PTEN, pAKT, total Akt in parental cell and their corresponding colonospheres.
Mentions: Colonospheres, considered to be surrogate tumors, are highly enriched in CSCs/CSLCs [22]. To determine whether miR-21 and its target protein PTEN are involved in regulating the functional properties of colonospheres, expressions of miR-21, PTEN and Akt, the downstream effectors of PTEN were analyzed in colonospheres generated from HCT116 and HT29. Both HCT116 and HT29 cell lines formed well-rounded spheroids (Figs. 2A & B; upper panel). Expression of miR-21, as determined by qRT-PCR, was found to be 4-5-fold higher in colonospheres, formed by both cell lines, compared to their corresponding parental cells (Figs. 2A & 2B; middle panel). On the other hand, Western-blot analysis revealed decreased expression of PTEN in colonospheres, compared to the corresponding parental cells (Figs. 2A & 2B; lower panel). As expected, reduction in PTEN in colonospheres was associated with increased activation of Akt, as demonstrated by marked increases in relative concentrations of p-Akt when compared with the corresponding parental cells (Figs. 2A & 2B lower. panel). Taken together, the results suggest that an increase in miR-21 in colonospheres that leads to reduction in PTEN activates Akt signaling pathway, which may play a role in regulating the tumorigenic properties of colonospheres that are enriched in CSCs/CSLCs.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America.

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.

Show MeSH
Related in: MedlinePlus