The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation
The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation
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DOI：
10.1038/onc.2010.417
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发表时间：
2011-01-01
期刊：
影响因子：
8
通讯作者：
Falasca, M.
中科院分区：
文献类型：
--
作者：
Pineiro, R.;Maffucci, T.;Falasca, M.
最近，孤儿受体G蛋白偶联受体55（GPR 55）已被提出作为一个潜在的大麻素受体，虽然仍有争议的生理作用。目前的证据表明GPR 55作为溶血磷脂酰肌醇（LPI）的受体的作用。在这项研究中，我们表明，GPR 55在几个前列腺癌和卵巢癌细胞系中表达，无论是在mRNA水平和蛋白质水平，它在调节增殖和锚定非依赖性生长的关键作用。我们进一步表明GPR 55介导LPI在前列腺癌和卵巢癌细胞中的作用。事实上，我们证明，LPI是能够诱导钙动员和激活Akt和细胞外信号调节激酶（ERK）1/2在这些细胞和药理学阻断GPR 55和它的下调使用特定的小干扰RNA强烈抑制这些过程。我们进一步确定了一个自分泌回路，其中LPI由胞质磷脂酶A2合成，由ATP结合盒转运蛋白ABCC 1/MRP 1泵出细胞，然后能够启动GPR 55下游的级联反应。总之，这些数据证明了癌细胞中LPI及其受体GPR 55在激活调节细胞增殖的自分泌环中的作用。这些发现可能对LPI作为一种新的癌症生物标志物及其受体GPR 55作为一种潜在的治疗靶点具有重要意义。Oncogene（2011）30，142-152; doi：10.1038/onc.2010.417; 2010年9月13日在线发表
Recently, the orphan receptor G protein-coupled receptor 55 (GPR55) has been proposed as a potential cannabinoid receptor, although controversy remains on its physiological roles. Current evidence suggests a role for GPR55 as a receptor for the lysophospholipid lysophosphatidylinositol (LPI). In this study, we show that GPR55 is expressed in several prostate and ovarian cancer cell lines, both at the mRNA and at the protein level, and that it has a critical role in regulating proliferation and anchorage-independent growth. We further show that GPR55 mediates the effects of LPI in prostate and ovarian cancer cells. Indeed we demonstrate that LPI is able to induce calcium mobilization and activation of Akt and extracellular signal-regulated kinase (ERK)1/2 in these cells and that both pharmacological blockade of GPR55 and its downregulation using specific small interfering RNA strongly inhibits these processes. We further identify an autocrine loop by which LPI is synthesized by cytosolic phospholipase A2, pumped out of the cell by the ATP-binding cassette transporter ABCC1/MRP1, and is then able to initialize cascades downstream of GPR55. All together, these data demonstrate a role of LPI and its receptor GPR55 in cancer cells in activating an autocrine loop that regulates cell proliferation. These findings may have important implications for LPI as a novel cancer biomarker and for its receptor GPR55 as a potential therapeutic target. Oncogene (2011) 30, 142-152; doi:10.1038/onc.2010.417; published online 13 September 2010