fk-866 and Colorectal-Neoplasms

The role and mechanism of the nicotinamide adenine dinucleotide (NAD. Real-time PCR, immunohistochemistry, western blotting, and analyses of datasets from Oncomine and Gene Expression Omnibus were conducted to assess the expression of NAMPT at the mRNA and protein levels in colorectal cancer. The Kaplan Meier plotter online tool was used to evaluate the prognostic role of NAMPT. Knockdown of NAMPT was performed to assess the role of NAMPT in colorectal cancer cell proliferation and tumorigenesis both in vitro and in vivo. Overexpression of NAMPT was used to evaluate impact of NAMPT on colorectal cancer cell proliferation in vitro. NAD. Our study indicated that the inhibition of NAMPT decreased proliferation capacity of colorectal cancer cells both in vitro and in vivo. Conversely, overexpression of NAMPT could promote cell proliferation in vitro. NAMPT inhibition induced β-catenin degradation by increasing Axin expression levels; this resulted in the inhibition of Wnt/β-catenin signaling and cell proliferation in colorectal cancer. The addition of nicotinamide mononucleotide, the enzymatic product of NAMPT, effectively reversed β-catenin protein degradation and inhibited growth. Similarly, the knockdown of Axin also decreased the cell death induced by the inhibition of NAMPT. In addition, we showed that colorectal cancer tissues harbored significantly higher levels of NAMPT than the levels harbored by paired normal tissues, especially in colorectal cancer stages I and II. And the overexpression of NAMPT was associated with unfavorable survival results.. Our findings reveal that NAMPT plays an important role in colorectal cancer proliferation via Wnt/β-catenin pathway, which could have vital implications for the diagnosis, prognosis and treatment of colorectal cancer.

Topics: Acrylamides; Adenomatous Polyposis Coli Protein; Animals; Axin Protein; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Cytokines; Female; Gene Knockdown Techniques; Humans; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Mutation; NAD; Neoplasm Invasiveness; Nicotinamide Phosphoribosyltransferase; Piperidines; Prognosis; Wnt Signaling Pathway

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus-mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase-3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.

Topics: Acrylamides; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Colorectal Neoplasms; Cytokines; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Piperidines; Signal Transduction; Sirtuin 1; Tumor Suppressor Protein p53

Cancer cells' resistance to drugs remains an important problem affecting cancer treatment strategies. We previously studied the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866's resistance mechanisms in the human colorectal cancer HCT116 cells. We established an acquired FK866-resistant cell line, HCT116R

Topics: Acrylamides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Cytokines; DNA Damage; Drug Resistance, Neoplasm; Enzyme Inhibitors; Exome Sequencing; Fluorouracil; Gamma Rays; Gene Expression Regulation, Neoplastic; Genomics; HCT116 Cells; Humans; Nicotinamide Phosphoribosyltransferase; Piperidines