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首页> 外文期刊>EBioMedicine >Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer
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Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

机译：脂肪酸2-羟基化抑制胃癌的生长并增加对顺铂的敏感性

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Background Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral ( R )-2-hydroxy FAs (( R )-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo . Findings FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with ( R )-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo . Moreover, ( R )-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that ( R )-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund Grants of NSF, NIH, and PAPD.
机译：背景大多数胃癌被诊断为晚期或转移性，预后和生存率均较差。在胃中高表达的脂肪酸2-羟化酶（FA2H）生成手性（R）-2-羟基FAs（（R）-2-OHFAs）并调节葡萄糖利用，这对细胞增殖和侵袭性至关重要。我们假设FA2H影响胃肿瘤的生长，并可能代表改善胃癌治疗的新目标。方法检测117例人胃肿瘤中的FA2H水平及其与肿瘤生长，转移和总生存的关系。通过体外和体内遗传和药理操作研究了其在调节肿瘤生长中的作用和潜在机制。与多个周围组织相比，胃肿瘤组织中的FA2H水平较低，并且与患者的临床病理状况有关，这一点已通过对多个已公开数据集的分析得到证实。 FA2H耗竭降低了肿瘤的化学敏感性，部分原因是由于AMPK的抑制和mTOR / S6K1 / Gli1途径的激活。相反，FA2H过度表达或用（R）-2-OHFAs处理则相反。与这些体外观察结果一致，FA2H敲低促进了体内肿瘤生长，并增加了体内Gli1的水平。此外，（R）-2-OHFA处理可显着降低胃肿瘤中的Gli1水平并增强肿瘤对顺铂的化学敏感性，同时减轻了化疗引起的小鼠体重减轻。解释我们的结果表明，FA2H在调节Hh信号和胃肿瘤生长中起重要作用，并表明（R）-2-OHFAs作为无毒的广谱药物可以有效地促进化学敏感性。 NSF，NIH和PAPD的资金补助。

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