2. Academic Validation
  3. Neurokinin-1 receptor drives PKCɑ-AURKA/N-Myc signaling to facilitate the neuroendocrine progression of prostate cancer

Neurokinin-1 receptor drives PKCɑ-AURKA/N-Myc signaling to facilitate the neuroendocrine progression of prostate cancer

  • Cell Death Dis. 2023 Jun 29;14(6):384. doi: 10.1038/s41419-023-05894-x.
Xiao-Wei Zhang 1 2 3,  Jing-Yi Li 2 4,  Lin Li 1 2 3,  Wen-Qian Hu 1 2 3,  Yan Tao 5,  Wen-Yan Gao 1 2 3,  Zi-Nuo Ye 1 2 3,  Hao-Yuan Jia 1 2 3,  Jia-Nan Wang 1 2 3,  Xiao-Kang Miao 2 3,  Wen-Le Yang 2 3,  Rui Wang 6 7,  Ling-Yun Mou 8 9 10
Affiliations

Affiliations

  • 1 School of Life Science Lanzhou University, 222 TianShui South Road, Lanzhou, 730000, P. R. China.
  • 2 Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou, 730000, China.
  • 3 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou, 730000, P. R. China.
  • 4 Departemnt of Biochemistry and Molecular Biology, School of basic medical sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, P. R. China.
  • 5 Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, 730000, China.
  • 6 Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou, 730000, China. wangrui@lzu.edu.cn.
  • 7 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou, 730000, P. R. China. wangrui@lzu.edu.cn.
  • 8 School of Life Science Lanzhou University, 222 TianShui South Road, Lanzhou, 730000, P. R. China. muly@lzu.edu.cn.
  • 9 Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou, 730000, China. muly@lzu.edu.cn.
  • 10 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou, 730000, P. R. China. muly@lzu.edu.cn.
PMID: 37385990 DOI: 10.1038/s41419-023-05894-x
Abstract

The widespread application of antiandrogen therapies has aroused a significant increase in the incidence of NEPC, a lethal form of the disease lacking efficient clinical treatments. Here we identified a cell surface receptor neurokinin-1 (NK1R) as a clinically relevant driver of treatment-related NEPC (tNEPC). NK1R expression increased in prostate Cancer patients, particularly higher in metastatic prostate Cancer and treatment-related NEPC, implying a relation with the progression from primary luminal adenocarcinoma toward NEPC. High NK1R level was clinically correlated with accelerated tumor recurrence and poor survival. Mechanical studies identified a regulatory element in the NK1R gene transcription ending region that was recognized by AR. AR inhibition enhanced the expression of NK1R, which mediated the PKCα-AURKA/N-Myc pathway in prostate Cancer cells. Functional assays demonstrated that activation of NK1R promoted the NE transdifferentiation, cell proliferation, invasion, and enzalutamide resistance in prostate Cancer cells. Targeting NK1R abrogated the NE transdifferentiation process and tumorigenicity in vitro and in vivo. These findings collectively characterized the role of NK1R in tNEPC progression and suggested NK1R as a potential therapeutic target.

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