ABSTRACT
Colon cancer is the second leading cause of cancer death. With over 153,000 new CRC cases predicted, it is the third most commonly diagnosed cancer. Early detection can lead to curative surgical intervention, but recurrent and late metastatic disease is frequently treated with chemotherapeutic options based on induction of DNA damage. Understanding mechanism(s) that regulate DNA damage repair within colon tumor cells is essential to developing effective therapeutic strategies. The Notch signaling pathway is known to participate in normal colon development and we have recently described a pathway by which Notch-1, Notch-3 and Smad may regulated EMT and stem-like properties in colon tumor cells, promoting tumorigenesis. Little is known about how Notch may regulate drug resistance. In this study, we used shRNA to generate colon tumor cells with loss of Notch-3 expression. These cells exhibited reduced expression of the base-excision repair proteins PARP1 and APE1, along with increased sensitivity to ara-c and cisplatin. These data point to a pathway in which Notch-3 signaling can regulate DNA repair within colon tumor cells and suggests that targeting Notch-3 may be an effective approach to rendering colon tumors sensitive to chemotherapeutic drugs.
Subject(s)
Colonic Neoplasms , Receptors, Notch , Humans , Receptors, Notch/metabolism , Drug Resistance, Neoplasm/genetics , Excision Repair , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , DNA/pharmacology , Cell Line, Tumor , DNA Repair/geneticsABSTRACT
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. It is also the third most common cancer diagnosis among men, and the second most common cancer diagnosis among women. Globally, CRC can account for nearly 694,000 annual deaths. It is widely appreciated that CRC is the result of dysregulated cellular pathways that promote an inappropriate stem-cell-like phenotype, apoptotic resistance, unchecked proliferation and metastatic spread. While no single pathway is responsible for all of these attributes, an array of recent studies suggests a pivotal role for abnormal Notch-1 signaling in CRC, in part due to interconnectivity of Notch with other pathways. This review will summarize recent evidence for a role of Notch signaling in CRC, will consider interconnectivity between Notch and other pathways involved in CRC and will discuss the possible utility of targeting Notch as a CRC therapeutic.
