Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer.

Ru-Hong Tu, Sheng-Ze Wu, Ze-Ning Huang, Qing Zhong, Yin-Hua Ye, Chao-Hui Zheng, Jian-Wei Xie, Jia-Bin Wang, Jian-Xian Lin, Qi-Yue Chen, Chang-Ming Huang, Mi Lin, Jun Lu, Long-Long Cao, Ping Li

Cancer research 2023 Dec 01

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Nerves can support tumor development by secreting neurotransmitters that promote cancer cell proliferation and invasion. 5-Hydroxytryptamine (5-HT) is a critical neurotransmitter in the gastrointestinal nervous system, and 5-HT signaling has been shown to play a role in tumorigenesis. Here, we found that expression of the 5-HT receptor HTR2B was significantly elevated in human gastric adenocarcinoma tissues compared with nontumor tissues, and high HTR2B expression corresponded to shorter patient survival. Both 5-HT and a specific HTR2B agonist enhanced gastric adenocarcinoma cell viability under metabolic stress, reduced cellular and lipid reactive oxygen species, and suppressed ferroptosis; conversely, HTR2B loss or inhibition with a selective HTR2B antagonist yielded the inverse tumor suppressive effects. In a patient-derived xenograft tumor model, HTR2B-positive tumors displayed accelerated growth, which was inhibited by HTR2B antagonists. Single-cell analysis of human gastric adenocarcinoma tissues revealed enrichment of PI3K/Akt/mTOR and fatty acid metabolism-related gene clusters in cells expressing HTR2B compared with HTR2B-negative cells. Mechanistically, HTR2B cooperated with Fyn to directly regulate p85 activity and trigger the PI3K/Akt/mTOR signaling pathway, which led to increased expression of HIF1α and ABCD1 along with decreased levels of lipid peroxidation and ferroptosis. Together, these findings demonstrate that HTR2B activity modulates PI3K/Akt/mTOR signaling to stimulate gastric cancer cell survival and indicate that HTR2B expression could be a potential prognostic biomarker in patients with gastric cancer. Nerve cancer cross-talk mediated by HTR2B inhibits lipid peroxidation and ferroptosis in gastric cancer cells and promotes viability under metabolic stress, resulting in increased tumor growth and decreased patient survival. ©2023 American Association for Cancer Research.

Citation

Ru-Hong Tu, Sheng-Ze Wu, Ze-Ning Huang, Qing Zhong, Yin-Hua Ye, Chao-Hui Zheng, Jian-Wei Xie, Jia-Bin Wang, Jian-Xian Lin, Qi-Yue Chen, Chang-Ming Huang, Mi Lin, Jun Lu, Long-Long Cao, Ping Li. Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer. Cancer research. 2023 Dec 01;83(23):3868-3885