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Dissection of the Mouse Pancreas for Histological Analysis and Metabolic Profiling
Published on: August 19, 2017
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Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and
Shu-Heng Jiang1, Jun Li2, Fang-Yuan Dong3
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, P.R. China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Gastroenterology
|March 19, 2017
Summary
Serotonin (5-HT) signaling promotes pancreatic ductal adenocarcinoma (PDAC) growth by increasing tumor cell glycolysis and proliferation via the HTR2B receptor. Inhibiting this pathway slowed tumor growth and improved survival in mice.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinomas (PDACs) exhibit metabolic stress due to desmoplasia and poor vascularity.
- Serotonin (5-HT), a neuromodulator, plays a role in tumorigenesis.
- The specific contribution of 5-HT signaling to pancreatic tumor growth remained to be elucidated.
Purpose of the Study:
- To investigate the role of serotonin (5-HT) signaling in the growth and metabolism of pancreatic tumors.
- To determine the involvement of the 5-HT receptor HTR2B in PDAC progression.
- To assess the therapeutic potential of targeting 5-HT signaling in PDAC.
Main Methods:
- Quantified 5-HT synthesis, packaging, and degradation proteins in mouse models (KPC), PDAC cell lines, and human tissue microarrays.
- Analyzed 5-HT receptor HTR2B expression and function, including effects of agonists, antagonists, and knockdown.
- Assessed 5-HT's impact on glycolysis, cell survival, apoptosis, and tumor growth in vitro and in vivo (xenografts and KPC mice).
Main Results:
- Increased 5-HT levels and elevated TPH1/decreased MAOA correlated with PDAC stage, size, and reduced patient survival.
- 5-HT promoted PDAC cell proliferation and inhibited apoptosis, primarily through the HTR2B receptor.
- Targeting HTR2B with antagonists (SB204741) or knockdown reduced tumor growth, glycolysis, and improved survival in mouse models.
Conclusions:
- Human PDACs exhibit elevated 5-HT levels and increased expression of its receptor, HTR2B.
- This 5-HT/HTR2B axis facilitates tumor glycolysis under metabolic stress, driving PDAC growth.
- Inhibition of the HTR2B pathway represents a potential therapeutic strategy for pancreatic cancer.
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