LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases.

Abstract Background Live kinase B1 (LKB1) is a tumor suppressor, which is mutated in Peutz-Jeghers syndrome (PJS) and in a variety of cancers. Lkb1 encodes serine-threonine kinase (STK) 11 that activates AMP-activated protein kinase (AMPK) and its 13 super-family members, hence 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, which promote tumorigenesis and development. On the other hand, LKB1 also participates in the maintenance of phenotypes and functions of normal cells through metabolic regulation. Scope of Review Given the important role of LKB1 in metabolic regulation, we provide an overview of the association of metabolic alterations in glycolysis, aerobic oxidation, pentose phosphate pathway (PPP), gluconeogenesis, glutamine, lipid, and serine induced by aberrant LKB1 signal in tumor progression, non-neoplastic diseases, and functions of immune cells. Major Conclusions In this review, we summarize layers of evidence demonstrating that disordered metabolisms in glucose, glutamine, lipid, and serine caused by deficiency of LKB1 promote carcinogenesis and non-neoplastic diseases. The metabolic reprogramming resulted from the loss of LKB1 confers cancer cells with growth or survival advantages. Nevertheless, it also brings about 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 under the regulation of LKB1 is conducive to the identification of therapeutic targets and the development of drug combination for the treatment of cancers, metabolic diseases, and the achievement of immunoregulation.