American Association for Cancer Research
can-23-1012_table_s1_suppst1.docx (14.07 kB)

Table S1 from Neurotransmitter Receptor HTR2B Regulates Lipid Metabolism to Inhibit Ferroptosis in Gastric Cancer

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journal contribution
posted on 2023-12-01, 08:22 authored by 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 receptors analyzed in this study


Natural Science Foundation of Fujian Province (Fujian Natural Science Foundation)

Fujian Province Innovation and Entrepreneurship Talents

Fujian research and training grants for young and middle-aged leaders in healthcare



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.

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