Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance.
Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance.
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DOI：
10.1038/s42003-020-01549-1
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发表时间：
2021-01-04
影响因子：
5.9
通讯作者：
Liu YN
中科院分区：
文献类型：
--
作者：
Chen WY;Wen YC;Lin SR;Yeh HL;Jiang KC;Chen WH;Lin YS;Zhang Q;Liew PL;Hsiao M;Huang J;Liu YN
神经生长因子(NGF)在恶性肿瘤的发生发展中起重要作用。然而，NGF在神经内分泌前列腺癌(NEPC)发生发展中的作用和调控机制尚不清楚。在这里，我们展示了雄激素剥夺疗法(ADT)刺激的转录因子ZBTB46通过ZBTB46介导的NGF转录激活上调NGF。在ADT后，NGF通过与G蛋白偶联受体-胆碱能受体M受体4(CHRM4)物理相互作用来调节NEPC的分化。药理作用的NGF拮抗剂和NGF基因敲除可显著抑制CHRM4介导的NEPC分化和AKT-MYCN信号的激活。在高级别和小细胞神经内分泌前列腺癌(SCNC)患者样本中，CHRM4刺激与ADT抵抗相关，并与NGF增加显著相关。我们的结果揭示了NGF在NEPC的发展中的作用，该作用与ZBTB46上调和CHRM4积累有关。我们的研究提供了证据，证明NGF-CHRM4轴有可能被认为是阻碍NEPC进展的治疗靶点。在这里，作者发现，在雄激素治疗的前列腺癌中，转录因子ZBTB46上调的NGF促进神经内分泌分化。他们表明，NGF与GPCRCHRM4相互作用，NGF和CHRM4在高转移性前列腺癌中均上调，靶向NGF降低了小鼠异种移植模型的治疗耐药性。
Nerve 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. Here, the authors discover that NGF, upregulated by transcription factor ZBTB46 in prostate cancer exposed to androgen therapy, promotes neuroendocrine differentiation. They show that NGF interacts with the GPCR CHRM4, that both NGF and CHRM4 are upregulated in highly metastatic prostate cancer and that targeting NGF reduces therapy resistance in a mouse xenograft model.