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.
Highlights
The emerging challenge in the treatment of colorectal cancer (CRC), the third most common cancer, is the relapse of the disease
We have reported that 5-Fluorouracil and Oxaliplatin (FU-Ox) resistant [chemo-resistant (CR)] colon cancer HCT116 and HT29 cells exhibit enrichment of CSCs/CSLCs and elevated levels of mature miR-21 and that miR-21 induce stemness in colon cancer cells [12]
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
Summary
The emerging challenge in the treatment of colorectal cancer (CRC), the third most common cancer, is the relapse of the disease. The presence of chemo- and radio-therapy resistant cancer stem/stem-like cells (CSCs/CSLCs) could be one of the underlying causes [1]. These cells are small population of undifferentiated tumor initiating cells having infinite self renewal capacity and are referred to as tumor initiating cells [2]. Downregulation of PTEN in different human tumors has been shown to result in resistance to conventional therapy and recurrence of cancer after initial treatment [4]. The PTEN-Akt pathway confers drug resistance to different malignancies including colorectal cancer [5,6,7,8]
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