Heterotrimeric G-protein, Gα16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer.
Heterotrimeric G-protein, Gα16, is a critical downstream effector of non-canonical Wnt signaling and a potent inhibitor of transformed cell growth in non small cell lung cancer.
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DOI：
10.1371/journal.pone.0076895
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Winn RA
中科院分区：
文献类型：
--
作者：
Avasarala S;Bikkavilli RK;Van Scoyk M;Zhang W;Lapite A;Hostetter L;Byers JT;Heasley LE;Sohn JW;Winn RA
G蛋白偶联受体是最大的细胞表面分子家族，在包括癌症在内的许多生物和病理过程中发挥重要作用/S早期的研究已经强调了Wnt7a通过其同源受体Frizzled9(GPCR)在抑制细胞增殖、锚定非依赖性生长和逆转非小细胞肺癌转化表型中的重要性，主要是通过激活肿瘤抑制因子PPARγ。然而，连接到这一重要的肿瘤抑制途径的G蛋白效应器还没有被确定，并且具有潜在的治疗兴趣。在这项研究中，通过使用两个独立的Wnt7a/Frizzled9特异性读出，我们确定Gα16是Wnt7a/Frizzled9信号的一个新的下游效应因子。有趣的是，在许多非小细胞肺癌细胞系中，Gα16的表达在信使RNA水平和蛋白水平上都被严重下调。此外，通过基因特异性敲除和表达Gα16的GTP酶缺陷型(Q212L)，我们还建立了Gα16作为一种新的非小细胞肺癌细胞增殖和锚定非依赖性生长调节因子。综上所述，我们的数据不仅证实了Gα16作为非典型Wnt信号通路的关键下游效应因子的重要性，而且也证实了它是治疗非小细胞肺癌的潜在靶点。
G-protein-coupled receptors (GPCR) are the largest family of cell surface molecules that play important role/s in a number of biological and pathological processes including cancers. Earlier studies have highlighted the importance of Wnt7a signaling via its cognate receptor Frizzled9, a GPCR, in inhibition of cell proliferation, anchorage-independent growth, and reversal of transformed phenotype in non small cell lung cancer primarily through activation of the tumor suppressor, PPARγ. However, the G-protein effectors that couple to this important tumor suppressor pathway have not been identified, and are of potential therapeutic interest. In this study, by using two independent Wnt7a/Frizzled9-specific read-outs, we identify Gα16 as a novel downstream effector of Wnt7a/Frizzled9 signaling. Interestingly, Gα16 expression is severely down-regulated, both at the messenger RNA levels and protein levels, in many non small cell lung cancer cell lines. Additionally, through gene-specific knock-downs and expression of GTPase-deficient forms (Q212L) of Gα16, we also establish Gα16 as a novel regulator of non small cell lung cancer cell proliferation and anchorage-independent cell growth. Taken together, our data not only establish the importance of Gα16 as a critical downstream effector of the non-canonical Wnt signaling pathway but also as a potential therapeutic target for the treatment of non small cell lung cancer.
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