Abstract
AbstractNerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.
Funder
Ministry of Science and Technology, Taiwan
Taipei Medical University
National Health Research Institutes
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference82 articles.
1. Chiarodo, A. National Cancer Institute roundtable on prostate cancer: future research directions. Cancer Res. 51, 2498–2505 (1991).
2. Chandrasekar, T., Yang, J. C., Gao, A. C. & Evans, C. P. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl. Androl. Urol. 4, 365–380 (2015).
3. Parimi, V., Goyal, R., Poropatich, K. & Yang, X. J. Neuroendocrine differentiation of prostate cancer: a review. Am. J. Clin. Exp. Urol. 2, 273–285 (2014).
4. Wang, H. T. et al. Neuroendocrine Prostate Cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis—a systematic review and pooled analysis. J. Clin. Oncol. 32, 3383–3390 (2014).
5. Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).
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