The Mary &, John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, 790 Commissioners Road East, Room A4‑921, London, ON, N6A 4L6, Canada.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Cell Commun Signal. 2024 Jun 6;22(1):310. doi: 10.1186/s12964-024-01689-5.
Liver Kinase B1 (LKB1), encoded by Serine-Threonine Kinase 11 (STK11), is a master kinase that regulates cell migration, polarity, proliferation, and metabolism through downstream adenosine monophosphate-activated protein kinase (AMPK) and AMPK-related kinase signalling. Since genetic screens identified STK11 mutations in Peutz-Jeghers Syndrome, STK11 mutants have been implicated in tumourigenesis labelling it as a tumour suppressor. In support of this, several compounds reduce tumour burden through upregulating LKB1 signalling, and LKB1-AMPK agonists are cytotoxic to tumour cells. However, in certain contexts, its role in cancer is paradoxical as LKB1 promotes tumour cell survival by mediating resistance against metabolic and oxidative stressors. LKB1 deficiency has also enhanced the selectivity and cytotoxicity of several cancer therapies. Taken together, there is a need to develop LKB1-specific pharmacological compounds, but prior to developing LKB1 inhibitors, further work is needed to understand LKB1 activity and regulation. However, investigating LKB1 activity is strenuous as cell/tissue type, mutations to the LKB1 signalling pathway, STE-20-related kinase adaptor protein (STRAD) binding, Mouse protein 25-STRAD binding, splicing variants, nucleocytoplasmic shuttling, post-translational modifications, and kinase conformation impact the functional status of LKB1. For these reasons, guidelines to standardize experimental strategies to study LKB1 activity, associate proteins, spliced isoforms, post-translational modifications, and regulation are of upmost importance to the development of LKB1-specific therapies. Therefore, to assess the therapeutic relevancy of LKB1 inhibitors, this review summarizes the importance of LKB1 in cell physiology, highlights contributors to LKB1 activation, and outlines the benefits and risks associated with targeting LKB1.
肝激酶 B1（LKB1）由丝氨酸-苏氨酸激酶 11（STK11）编码，是一种主激酶，通过下游腺苷单磷酸激活蛋白激酶（AMPK）和 AMPK 相关激酶信号传导来调节细胞迁移、极性、增殖和代谢。由于遗传筛选发现了 Peutz-Jeghers 综合征中的 STK11 突变，STK11 突变体被认为与肿瘤发生有关，将其标记为肿瘤抑制因子。支持这一点的是，几种化合物通过上调 LKB1 信号来降低肿瘤负担，并且 LKB1-AMPK 激动剂对肿瘤细胞具有细胞毒性。然而，在某些情况下，它在癌症中的作用是矛盾的，因为 LKB1 通过介导对代谢和氧化应激物的抗性来促进肿瘤细胞存活。LKB1 缺乏也增强了几种癌症疗法的选择性和细胞毒性。总之，需要开发 LKB1 特异性药理学化合物，但在开发 LKB1 抑制剂之前，需要进一步研究以了解 LKB1 的活性和调节。然而，由于细胞/组织类型、LKB1 信号通路的突变、STE-20 相关激酶衔接蛋白（STRAD）结合、Mouse protein 25-STRAD 结合、剪接变体、核质穿梭、翻译后修饰和激酶构象都会影响 LKB1 的功能状态，因此研究 LKB1 的活性是很费力的。出于这些原因，制定标准化实验策略以研究 LKB1 活性、相关蛋白、剪接异构体、翻译后修饰和调节的指南对于开发 LKB1 特异性疗法至关重要。因此，为了评估 LKB1 抑制剂的治疗相关性，本综述总结了 LKB1 在细胞生理学中的重要性，强调了 LKB1 激活的贡献因素，并概述了靶向 LKB1 的益处和风险。
