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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI200391

Targeting tryptophan hydroxylase 1 restricts growth and suppresses plasticity in neuroendocrine prostate cancer

Jing Wei,1 Jing Wang,1 Jingrui Chen,1 Michelle Zhang,2 Chia-Hui Chen,1 Tianjie Pu,1 Alivia O'Brien,1 Sephtis Hargrove,3 Eva Corey,4 Tzu-Ping Lin,5 Allen C. Gao,6 and Boyang Jason Wu1

1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

Find articles by Chen, C. in: PubMed | Google Scholar

1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

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1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

Find articles by Corey, E. in: PubMed | Google Scholar |

1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

Find articles by Lin, T. in: PubMed | Google Scholar

1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

Find articles by Gao, A. in: PubMed | Google Scholar

1Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

2Leigh High School, San Jose, United States of America

3Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, United States of America

4Department of Urology, University of Washington, Seattle, United States of America

5Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

6Department of Urologic Surgery, UC Davis, Sacramento, United States of America

Find articles by Wu, B. in: PubMed | Google Scholar

Published September 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI200391.
Copyright © 2026, Wei et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 17, 2026 - Version history
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Abstract

Advanced prostate cancer has increasingly developed a lethal neuroendocrine form, small cell/neuroendocrine prostate cancer (NEPC), as a consequence of the widespread use of highly potent androgen receptor signaling inhibitors in castration-resistant disease. The molecular mechanisms remain unclear and no effective therapies currently exist. We report that tryptophan hydroxylase 1 (TPH1), the enzyme responsible for peripheral serotonin biosynthesis — a neurotransmitter enriched in neuroendocrine tumors and a classical neuroendocrine biomarker — was upregulated in both de novo and therapy-induced human NEPC. TPH1 upregulation was necessary and sufficient for neuroendocrine differentiation and the NEPC phenotype through its enzymatic activity. Silencing TPH1 suppressed neuroendocrine plasticity and various aggressive behaviors of NEPC cells, including proliferation, invasion, sphere formation, and NEPC tumor xenograft growth. Mechanistically, TPH1 activated mTOR via intracellular serotonin-dependent serotonylation of mTOR at glutamine 2453, which triggered the induction of FOXM1 and E2F1 to drive NEPC differentiation and growth. Importantly, pharmacological inhibition of TPH1 using the clinically available inhibitor LX1606 effectively restricted growth and neuroendocrine marker expression in multiple NEPC cell lines and patient-derived xenografts. Collectively, these findings characterize TPH1’s contribution to NEPC and suggest TPH1 as a potential therapeutic target.

Graphical Abstract
graphical abstract
Supplemental material

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Version history
  • Version 1 (September 17, 2026): In-Press Preview
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