Inhibiting G protein βγ signaling blocks prostate cancer progression and enhances the efficacy of paclitaxel.
Inhibiting G protein βγ signaling blocks prostate cancer progression and enhances the efficacy of paclitaxel.
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DOI：
10.18632/oncotarget.16428
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
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作者：
Paudyal P;Xie Q;Vaddi PK;Henry MD;Chen S
G蛋白偶联受体（GPCR）的异常激活与前列腺癌进展有关，但靶向它们一直具有挑战性，因为多种GPCR参与癌症进展。在这项研究中，我们测试了通过多个GPCR会聚的枢纽-G蛋白Gβγ亚基阻断信号传导的效果。在几种去势抵抗性前列腺癌细胞系（即PC 3、DU 145和22 Rv 1）中抑制Gβγ信号传导，在体外损害细胞生长和迁移，并在裸鼠中停止肿瘤生长和转移。Gβγ信号传导的阻断还通过减少体外肿瘤球形成和裸鼠有限稀释试验中的肿瘤形成来减少前列腺癌干细胞样活性。此外，在体外和体内，Gβγ阻断增强前列腺癌细胞对紫杉醇治疗的敏感性。总之，我们的结果确定了Gβγ在调节前列腺癌干细胞样活性中的新功能，并证明靶向Gβγ信号传导是阻断前列腺癌进展和增强对化疗反应的有效方法。
Aberrant activation of G protein-coupled receptors (GPCRs) is implicated in prostate cancer progression, but targeting them has been challenging because multiple GPCRs are involved in cancer progression. In this study, we tested the effect of blocking signaling via a hub through which multiple GPCRs converge — the G-protein Gβγ subunits. Inhibiting Gβγ signaling in several castration-resistant prostate cancer cell lines (i.e. PC3, DU145 and 22Rv1), impaired cell growth and migration in vitro, and halted tumor growth and metastasis in nude mice. The blockade of Gβγ signaling also diminished prostate cancer stem cell-like activities, by reducing tumorsphere formation in vitro and tumor formation in a limiting dilution assay in nude mice. Furthermore, Gβγ blockade enhanced the sensitivity of prostate cancer cells to paclitaxel treatment, both in vitro and in vivo. Together, our results identify a novel function of Gβγ in regulating prostate cancer stem-cell-like activities, and demonstrate that targeting Gβγ signaling is an effective approach in blocking prostate cancer progression and augmenting response to chemotherapy.