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Gamma-secretase inhibitor, a potential target therapy for MUC2-positive colorectal carcinoma
1Department of Pathology, School of Medicine, Southeast University, Dingjiaqiao Road, Nanjing, Jiangsu Province, China. hplwpp@yahoo.cn
Abstract:
Notch signaling may be mechanistically involved the colorectal carcinogenesis. Blocking of Notch signaling by gamma-secretase inhibitor may constitute a novel molecular therapy for cancer. In the present study, we blocked the Notch signaling by DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, a gamma-secretase inhibitor) and investigated the effects on the proliferative and invasive potential of human colorectal cancer LS174T cells, a goblet cell-like colorectal cancer cell line which produces high-levels of MUC2 continuously. DAPT inhibited the proliferation and invasion of LS174T cells. Blocking of Notch signaling by DAPT could down-regulate its downstream target gene Hes1, while enhancing the expression of Math1 and MUC2 in LS174T cells. In conclusion, we demonstrated that blocking of Notch signaling by DAPT could inhibit the proliferation and invasion of human colorectal cancer LS174T cells and suggested that gamma-secretase inhibitors may provide a targeted therapy for MUC2-positive colorectal tumors.
Insights
Blocking Notch signaling with DAPT, a gamma-secretase inhibitor, reduced colorectal cancer cell growth and invasion. This targeted therapy may be effective for MUC2-positive colorectal tumors.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Notch signaling is implicated in colorectal carcinogenesis.
- Gamma-secretase inhibitors offer a potential molecular therapy for cancer.
Purpose of the Study:
- To investigate the effects of DAPT, a gamma-secretase inhibitor, on colorectal cancer cell proliferation and invasion.
- To explore DAPT's impact on Notch signaling pathway components and MUC2 expression in LS174T cells.
Main Methods:
- Utilized DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) to block Notch signaling.
- Assessed the proliferative and invasive potential of human colorectal cancer LS174T cells.
- Analyzed the expression of Hes1, Math1, and MUC2 genes.
Main Results:
- DAPT significantly inhibited the proliferation and invasion of LS174T cells.
- Blocking Notch signaling with DAPT downregulated Hes1 expression.
- DAPT treatment enhanced the expression of Math1 and MUC2 in LS174T cells.
Conclusions:
- Inhibition of Notch signaling by DAPT effectively suppresses colorectal cancer cell proliferation and invasion.
- Gamma-secretase inhibitors like DAPT show promise as targeted therapies for MUC2-positive colorectal tumors.
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