A Novel Inhibitor Of Sirtuin: Elucidation Of Mode Of Action And Molecular Pathway In Colorectal Cancer Cell Line
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Date
2017-08
Authors
Tan, Yi Jer
Journal Title
Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Although most patients are responsive to standard chemotherapy treatments at the initial stage of diagnosis, many succumb to relapse due to acquired chemoresistance, hence driving the need for the development of novel therapeutic agents for colorectal cancer. Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are important targets as they have been implicated in tumour progression. SIRT1 is overexpressed in colorectal cancer, while SIRT2 represses tumour suppressor genes and play key roles in cancer cell survival. BZD9L1 is a novel SIRT1 and SIRT2 inhibitor with reported anti-cancer activities. This project aimed to investigate the molecular players involved in BZD9L1-mediated colorectal cancer cell inhibition as well as its regulation of cancer signaling pathways. The effect of BZD9L1 on cell survival, proliferation, migration, cell cycle, senescence, apoptosis and the molecular players mediating these outcomes were studied in HCT116 and HT-29 colorectal cancer cell lines. BZD9L1 reduced the viability of HCT116 and HT-29 cells but displayed non-significant effect on the cell viability of normal human colon epithelial CCD841 CoN cells. BZD9L1 significantly reduced cell proliferation and inhibited cell migration in increasing doses in both cell lines. However the compound had no effect on cell cycle distribution and cellular senescence. In addition, BZD9L1 induced cleavage of PARP and chromatin condensation, indicating apoptosis in both cell lines. BZD9L1 also upregulated the transcription factors associated with Notch, NF- kB, Myc/Max, ERK and JNK pathways in HCT116 but downregulated the transcription factors related to Wnt, Notch, p53, TGF, NF-kB, Myc/Max, HIF and ERK pathways in HT-29 cells, highlighting bifunctional roles of these cancer pathways which result in the same treatment outcome. In conclusion, BZD9L1 exhibited anti-cancer activities as a cytotoxic drug that mediates apoptotic cell death in colorectal cancer. Hence, inhibiting SIRT1 and SIRT2 activities using BZD9L1 could be a promising therapeutic strategy in the treatment of colorectal cancer.
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Keywords
Colorectal cancer is one of the most , common types of cancer worldwide.