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.

中文翻译：

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GPR55 信号传导促进小鼠胰腺癌细胞增殖和肿瘤生长，其抑制作用会增强吉西他滨的作用。


胰腺癌患者的预期寿命在过去 40 年里没有发生实质性变化，因为可用的治疗方法很少且大多只是姑息治疗。由于五年生存率仍维持在5%左右，迫切需要识别新的药理靶点并开发新的治疗策略。在这里，我们证明使用遗传和药理学方法抑制 G 蛋白偶联受体 GPR55 可减少体外和体内胰腺癌细胞的生长，我们认为这可能代表一种抑制胰腺导管腺癌 (PDAC) 进展的新策略。具体来说，我们发现在 PDAC 的 KRAS ^WT/G12D /TP53 ^WT/R172H /Pdx1-Cre ^+/+ (KPC) 小鼠模型中，Gpr55 的基因消除可显着延长生存期。重要的是，用 GPR55 拮抗剂大麻二酚 (CBD) 和吉西他滨（GEM，治疗 PDAC 最常用的药物之一）联合治疗的 KPC 小鼠，与单独用载体或 GEM 治疗的小鼠相比，存活时间延长了近三倍。从机制上讲，GPR55 的敲低或药理抑制会降低 PDAC 细胞中锚定依赖性和独立生长、细胞周期进展、丝裂原激活蛋白激酶 (MAPK) 信号的激活以及核糖核苷酸还原酶的蛋白质水平。与此一致的是，Gpr55 的基因消除降低了 KPC 小鼠肿瘤细胞的增殖、MAPK 信号传导和核糖核苷酸还原酶 M1 的水平。 CBD 和 GEM 的组合抑制了 KPC 小鼠的肿瘤细胞增殖，并且与体外和体内 GEM 耐药性发展的机制相反。 最后，我们证明肿瘤抑制因子 p53 通过调节 microRNA miR34b-3p 来调节 GPR55 蛋白表达。我们的结果证明了 p53 下游的 GPR55 在 PDAC 进展中发挥的重要作用。此外，我们的数据表明，目前已批准用于医疗用途的 CBD 和 GEM 的组合可能会在临床试验中进行测试，作为一种有前景的新型治疗方法，以改善 PDAC 患者的预后。