Abstract
Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer.
Highlights
Breast cancer is currently the most frequently diagnosed cancer and the leading cause of cancer-related death in women worldwide, accounting for 23% of cancer diagnoses and 14% of cancer deaths each year [1]
To evaluate the cytotoxicity of 5-FU and the effect of small interfering RNA mediated silencing of epithelial cell adhesion molecule (EpCAM), MCF-7 cells were incubated with 7.5 mg/ml and 20 mg/ml 5-FU combined with or without si-EpCAM for 48 h
We showed that knockdown of EpCAM significantly increased the chemosensitivity of MCF-7 cells to 5-FU in vitro through a mechanism involving the si-EpCAM-mediated modulation of the expression of anti-apoptotic factors in tumor cells and the induction of apoptosis and cell cycle arrest at S phase
Summary
Breast cancer is currently the most frequently diagnosed cancer and the leading cause of cancer-related death in women worldwide, accounting for 23% of cancer diagnoses and 14% of cancer deaths each year [1]. The development of effective therapies against cancer is important. Despite the steady improvement of 5-FU-basedtreatment regimens, the patient response rate to 5-FU-based chemotherapy remains modest mainly due to the development of drug resistance. One major resistance mechanism utilized by tumor cells is to resist drug-induced cell death through the disruption of apoptotic pathways. There is an urgent need to develop chemosensitizers capable of increasing the sensitivity of tumor cells to chemotherapy. For this purpose, it is essential to understand the mechanisms of drug resistance and to discover novel strategies to further improve the effectiveness of 5-FU
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