1. Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer
- Author
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Chen, Bo, Xu, Pengfei, Yang, Joy C, Nip, Christopher, Wang, Leyi, Shen, Yuqiu, Ning, Shu, Shang, Yufeng, Corey, Eva, Gao, Allen C, Gestwicki, Jason E, Wei, Qiang, Liu, Liangren, and Liu, Chengfei
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Biotechnology ,Prostate Cancer ,Urologic Diseases ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Humans ,Male ,Animals ,Mice ,Drug Resistance ,Neoplasm ,Cell Line ,Tumor ,Prostatic Neoplasms ,Cell Proliferation ,Gene Expression Regulation ,Neoplastic ,Cell Lineage ,Nerve Tissue Proteins ,Xenograft Model Antitumor Assays ,Cell Plasticity ,Receptors ,Cell Surface ,Prognosis ,Membrane Glycoproteins ,Intracellular Signaling Peptides and Proteins ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.
- Published
- 2024