Abstract 5446: Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival

Abstract

Abstract The hormone serotonin is known as 5-hydroxytryptamine. It is a precursor of melatonin, derived from the amino acid tryptophan. Serotonin acts as a neurotransmitter and modulates several key functions in the human body, such as appetite, mood and sleep. Apart from its important roles in the central nervous system (CNS), serotonin regulates various extra-neuronal pathophysiological functions. Serotonin is synthesized by Enterochromaffin cells of the gut, mostly stored in platelets and about 2% of free serotonin released in the blood. The role of peripheral serotonin in adipocytes, pancreatic cells, macrophages and liver cells is not fully understood. In the current study, we investigated the role of serotonin in liver cancer cell signaling and liver cancer cell growth. Treatment of serotonin in liver cancer cells HepG2 and SK-Hep1 induced autophagy markers and effectors such as LC3 I/II, phospho-4EBP1, ATG3 and Beclin1, and, increased cell proliferation and cell survival. AKT/mTOR pathway controls cellular autophagy and our results demonstrated that exposure of serotonin to liver cancer cells inactivates AKT/mTOR signaling and induced autophagy. Also, we demonstrate that serotonin also activates Notch signaling pathway as evident by induction of Notch target gene Hes1. Notch inhibitors Avagacestat 2 and FLI-06 inhibited serotonin-mediated Notch signaling and cellular autophagy. Furthermore, by the activation of Notch signaling, serotonin-induced oleic acid-mediated cell steatosis in both HepG2 and SK-Hep1 liver cancer cells. In addition, treatment of serotonin also induced autophagy modulator proteins such as SIRT1 and Tumor Necrosis Factor Alpha Inducing Protein 8 (TNFAIP8) which participate in the modulation of cellular autophagy and cell survival. Taken together our data suggested that peripheral serotonin regulates liver cancer cell steatosis, cells survival and may promote liver carcinogenesis by the modulation of AKT/mTOR and Notch signaling pathways. Citation Format: Suresh Niture, Deepak Kumar. Serotonin modulates AKT-mTOR and Notch signaling pathways, promotes liver cancer cell steatosis and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5446.