Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China.
School of Life Sciences, Henan University, Kaifeng, 475004, China.
Mol Metab. 2021 Feb;44:101131. doi: 10.1016/j.molmet.2020.101131. Epub 2020 Dec 3.
Live kinase B1 (LKB1) is a tumor suppressor that is mutated in Peutz-Jeghers syndrome (PJS) and a variety of cancers. Lkb1 encodes serine-threonine kinase (STK) 11 that activates AMP-activated protein kinase (AMPK) and its 13 superfamily members, regulating multiple biological processes, such as cell polarity, cell cycle arrest, embryo development, apoptosis, and bioenergetics metabolism. Increasing evidence has highlighted that deficiency of LKB1 in cancer cells induces extensive metabolic alterations that promote tumorigenesis and development. LKB1 also participates in the maintenance of phenotypes and functions of normal cells through metabolic regulation.
Given the important role of LKB1 in metabolic regulation, we provide an overview of the association of metabolic alterations in glycolysis, aerobic oxidation, the pentose phosphate pathway (PPP), gluconeogenesis, glutamine, lipid, and serine induced by aberrant LKB1 signals in tumor progression, non-neoplastic diseases, and functions of immune cells.
In this review, we summarize layers of evidence demonstrating that disordered metabolisms in glucose, glutamine, lipid, and serine caused by LKB1 deficiency promote carcinogenesis and non-neoplastic diseases. The metabolic reprogramming resulting from the loss of LKB1 confers cancer cells with growth or survival advantages. Nevertheless, it also causes a metabolic frangibility for LKB1-deficient cancer cells. The metabolic regulation of LKB1 also plays a vital role in maintaining cellular phenotype in the progression of non-neoplastic diseases. In addition, lipid metabolic regulation of LKB1 plays an important role in controlling the function, activity, proliferation, and differentiation of several types of immune cells. We conclude that in-depth knowledge of metabolic pathways regulated by LKB1 is conducive to identifying therapeutic targets and developing drug combinations to treat cancers and metabolic diseases and achieve immunoregulation.
活激酶 B1（LKB1）是一种肿瘤抑制因子，在 Peutz-Jeghers 综合征（PJS）和多种癌症中发生突变。Lkb1 编码丝氨酸-苏氨酸激酶（STK）11，可激活 AMP 激活的蛋白激酶（AMPK）及其 13 个超家族成员，调节多种生物过程，如细胞极性、细胞周期停滞、胚胎发育、细胞凋亡和生物能量代谢。越来越多的证据表明，癌细胞中 LKB1 的缺失会引起广泛的代谢改变，从而促进肿瘤的发生和发展。LKB1 还通过代谢调节参与维持正常细胞的表型和功能。
鉴于 LKB1 在代谢调节中的重要作用，我们概述了异常 LKB1 信号引起的糖酵解、有氧氧化、磷酸戊糖途径（PPP）、糖异生、谷氨酰胺、脂质和丝氨酸代谢改变与肿瘤进展、非肿瘤性疾病和免疫细胞功能的关系。
在本综述中，我们总结了大量证据表明，LKB1 缺失引起的葡萄糖、谷氨酰胺、脂质和丝氨酸代谢紊乱促进了致癌和非肿瘤性疾病的发生。LKB1 缺失导致的代谢重编程赋予了癌细胞生长或存活优势。然而，它也使 LKB1 缺陷型癌细胞的代谢变得脆弱。LKB1 的代谢调节在非肿瘤性疾病的进展中对维持细胞表型也起着至关重要的作用。此外，LKB1 的脂质代谢调节在控制几种类型免疫细胞的功能、活性、增殖和分化方面发挥着重要作用。我们的结论是，深入了解 LKB1 调节的代谢途径有助于确定治疗靶点并开发联合药物来治疗癌症和代谢性疾病，并实现免疫调节。
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