GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine
GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine
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DOI：
10.1038/s41388-018-0390-1
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发表时间：
2018-12-06
期刊：
影响因子：
8
通讯作者：
Falasca, M.
中科院分区：
文献类型：
--
作者：
Ferro, R.;Adamska, A.;Falasca, M.
在过去的40年里，胰腺癌患者的预期寿命没有发生实质性变化，因为很少有而且大多数只是姑息治疗。由于5年生存率保持在5%左右，因此迫切需要鉴定新的药理学靶点和开发新的治疗策略。在这里，我们证明了G蛋白偶联受体GPR 55的抑制，使用遗传和药理学方法，减少胰腺癌细胞的生长在体外和体内，我们提出，这可能是一种新的策略，以抑制胰腺导管腺癌（PDAC）的进展。具体而言，我们表明，在PDAC的KRAS（WT/G12 D）/TP 53（WT/）（R172 H）/Pdx 1-Cre（+/+）（KPC）小鼠模型中，Gpr 55的遗传消除显著延长了存活。重要的是，用GPR 55拮抗剂大麻二酚（CBD）和吉西他滨（GEM，治疗PDAC的最常用药物之一）的组合治疗的KPC小鼠，与单独用媒介物或GEM治疗的小鼠相比，存活时间长近三倍。在机制上，GPR 55的敲低或药理学抑制降低了PDAC细胞中的锚定依赖性和独立性生长、细胞周期进展、促分裂原活化蛋白激酶（MAPK）信号传导的活化和核糖核苷酸还原酶的蛋白水平。与此一致，Gpr 55的基因切除减少了KPC小鼠中肿瘤细胞的增殖、MAPK信号传导和核糖核苷酸还原酶M1水平。CBD和GEM的组合抑制了KPC小鼠中的肿瘤细胞增殖，并且它对抗了体外和体内对GEM产生耐药性的机制。最后，我们证明了肿瘤抑制因子p53通过调节microRNA miR 34 b-3 p来调节GPR 55蛋白的表达。我们的研究结果表明，GPR 55下游的p53在PDAC进展中发挥了重要作用。此外，我们的数据表明，CBD和GEM的组合，目前都批准用于医疗用途，可能会在临床试验中测试作为一种新的有前途的治疗，以改善PDAC患者的结果。
The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRAS(WT/G12D)/TP53(WT/)(R172H)/Pdx1-Cre(+/+) (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.