Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival.
Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival.
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DOI：
10.1038/s41598-017-02918-3
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发表时间：
2017-06-08
影响因子：
4.6
通讯作者：
Lokeshwar BL
中科院分区：
文献类型：
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作者：
Hoy JJ;Kallifatidis G;Smith DK;Lokeshwar BL
非典型的C-X-C趋化因子受体7(CXCR7)被认为支持包括前列腺癌在内的多种癌症的侵袭性表型。然而，驱动该受体在癌症中过度表达的机制却知之甚少。本研究探讨雄激素受体(AR)在调节CXCR7中的作用。雄激素缺乏或AR抑制显著增加雄激素反应性前列腺癌CXCR7的表达，伴随着表皮生长因子受体(EGFR)介导的促有丝分裂信号的增强，通过雄激素非依赖的信号程序促进肿瘤细胞的存活。使用多种方法，我们证明了AR直接与CXCR7启动子结合，抑制转录。簇状规则间隔短回文重复序列(CRISPR)指导的Cas9核酸酶介导的CXCR7基因编辑揭示了前列腺癌细胞依赖于CXCR7的增殖、存活和克隆形成能力。CRISPR-Cas9基因编辑导致CXCR7表达缺失，导致细胞增殖停止，EGFR信号严重受损，细胞开始衰老。对突变的表达CXCR7的LNCaP细胞克隆的鉴定表明，细胞内信号转导发生改变，球体形成能力降低。我们的结果表明，CXCR7是一个潜在的靶点，辅助治疗与雄激素剥夺治疗(ADT)相结合，以防止雄激素非依赖性肿瘤细胞的生存。
The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.