文章：

LKB1-AMPK通路：肿瘤抑制中的代谢和生长控制

The LKB1–AMPK pathway: metabolism and growth control in tumour suppression

原文发布日期：2009-08-01

DOI: 10.1038/nrc2676

类型: Review Article

开放获取: 否

要点：

1. The serine–threonine liver kinase B1 (LKB1) is inactivated in Peutz–Jeghers syndrome and a large percentage of sporadic non-small cell lung carcinomas and cervical carcinomas.
2. LKB1 acts a master upstream kinase, directly phosphorylating and activating AMP-activated protein kinase (AMPK) and a family of 12 related kinases that have crucial roles in cell growth, metabolism and polarity.
3. The LKB1–AMPK pathway serves as a metabolic checkpoint in the cell, arresting cell growth in conditions of low intracellular ATP levels, such as in low nutrient conditions.
4. One of the central mitogenic pathways that is suppressed by LKB1 and AMPK signalling is the mTOR complex 1 pathway, which is inhibited through AMPK phosphorylation of tuberous sclerosis complex 2 and regulatory associated protein of mTOR (raptor).
5. Overnutrition and hyperglycaemia can suppress LKB1–AMPK signalling, which might contribute to an increased cancer risk in patients who are obese or diabetic. Conversely, activation of LKB1–AMPK signalling might contribute to the suppression of cancer risk that is associated with exercise and caloric restriction. Will AMPK-activating drugs, including existing diabetes therapeutics, find clinical usefulness as anticancer agents?

要点翻译：

1. 丝氨酸-苏氨酸肝激酶B1（LKB1）在珀茨-杰格斯综合征、大部分散发性非小细胞肺癌及宫颈癌中处于失活状态。
2. LKB1作为上游主激酶，直接磷酸化并激活AMP活化蛋白激酶（AMPK）及其家族12种相关激酶，这些激酶在细胞生长、代谢和极性调控中发挥关键作用。
3. LKB1-AMPK通路构成细胞内的代谢检查点，在细胞内ATP水平偏低（如营养不足）时阻滞细胞生长。
4. 该通路通过AMPK磷酸化结节性硬化复合物2和mTOR调控相关蛋白（raptor），进而抑制核心促有丝分裂通路——mTOR复合物1通路。
5. 营养过剩和高血糖会抑制LKB1-AMPK信号传导，这可能增加肥胖或糖尿病患者患癌风险。反之，激活LKB1-AMPK信号可能有助于实现运动与热量限制相关的癌症风险抑制。包括现有糖尿病治疗药物在内的AMPK激活剂，能否在临床上作为抗癌药物发挥作用？

英文摘要：

In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine–threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.

摘要翻译： 

在过去十年中，对人类肿瘤抑制因子LKB1的研究揭示了一条新的信号通路，该通路将细胞代谢与生长控制和细胞极性联系起来。LKB1编码一种丝氨酸-苏氨酸激酶，可直接磷酸化并激活AMPK，后者是中枢代谢传感器。AMPK在肝脏、肌肉和脂肪组织等特异性代谢组织中调节脂质、胆固醇和葡萄糖代谢。这一功能使AMPK成为糖尿病治疗的关键靶点。AMPK与多种肿瘤抑制因子的关联提示，使用已建立的糖尿病药物对该通路进行干预，值得在癌症患者中进一步研究。

原文链接：

The LKB1–AMPK pathway: metabolism and growth control in tumour suppression