Targeting iNAMPT to Break the Obesity-Associated Liver Cancer Link: An In Vitro and In Vivo Approach




Thornton, Kelly Rene

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Background: Studies have shown that obesity is linked to liver cancer through metabolic mechanisms. Obesity can promote tumor growth through metabolic impairment, decreased lipid metabolism, and the interference of energy balance in the liver. NAMPT is an enzyme expressed in the liver and is involved in the progression of tumors in obesogenic environments. iNAMPT is known to be the rate-limiting enzyme in the synthesis of NAD, an essential coenzyme involved in ATP synthesis which promotes a pro-growth environment in the context of obesity. Because iNAMPT and cellular energetics, a hallmark of cancer, plays an important role in liver cancer progression, it has become a target for therapies focused on inhibiting its behavior in cancer cells. The objective of this study was to determine the contribution of NAD biosynthesis in obesity-induced liver cancer progression. Methods: Cell studies were conducted with serum from mice randomized to a diet-induced obesity (OB) or control chow (CR) + FK866 (iNAMPT inhibitor) in SNU, HepG2 human liver cancer cells and Hepa 1-6 murine cells. Analysis of proteins pAkt and pERK was performed by immunoblot. Proliferation, ROS, cytotoxicity, and invasion were also measured in liver cancer cells. For the mouse model, C57/BL mice were randomized to OB chow or CR chow. At 21 weeks of age, mice were injected subcutaneously with Hepa 1-6 liver cancer cells. At 23 weeks, mice received an I.P. injection of FK8666 (30 mg/kg) for 2 weeks. Tumor and mouse weights were measured. Results: Cells exposed to OB sera increased proliferation, LDH secretion, ROS, invasion. FK866 decreased proliferation, LDH secretion, ROS, and invasion in all liver cancer cells. Cells exposed to NW sera and OB + FK866 resulted in more LDH suggesting increased apoptosis compared to OB sera. OB sera increased phosphorylation of Akt which was suppressed by FK866 compared to OB. In liver cancer cells, physiological and cellular signaling were differentially affected when inhibiting NAD biosynthesis in an in vitro model of obesity and liver cancer. In vivo, OB mice weighed significantly more than mice fed a control diet. In addition, 66% of OB mice developed tumors compared to 16% in CR mice. Impact: Identifying pre-clinical strategies to reverse the impact of obesity on liver cancer progression is important due to the strongly increased risk of liver cancer and its poor prognosis. Future translation research studies will build from this pre-clinical foundational research.



hepatocellular carcinoma, liver cancer, obesity, liver, cancer, FK866, NAMPT, NAD, animal model, cell culture


Thornton, K. R. (2023). Targeting iNAMPT to break the obesity-associated liver cancer link: An in vitro and in vivo approach. Honors College, Texas State University.


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