Mutations in serine-threonine kinase 11 (STK11) and liver kinase B1 (LKB1) are linked to disease progression in Peutz-Jeghers syndrome (PJS), a condition that can lead to cancer. Research indicates that the inactivation of LKB1 triggers tumor formation in animal models, whereas its overexpression reduces microvessel density, tumor burden, and cell proliferation, positioning LKB1 as a tumor suppressor. However, other studies suggest that LKB1 promotes tumorigenesis through mechanisms such as ROS scavenging, DNA repair machinery activation, and autophagy. This paradoxical role of LKB1 in tumor biology is explored in a review published in the Genes & Diseases journal by researchers from The Mary & John Knight Translational Ovarian Cancer Research Unit at Western University, Canada.
The review delves into both the tumor-suppressing and promoting functions of LKB1 signaling, offering insights into the biochemical processes that govern its activity. It also highlights the therapeutic potential of targeting LKB1 signaling in cancer treatment. Somatic mutations in LKB1, along with structural variants, amplifications, and deletions have been identified across various cancer types. These mutations often coincide and synergize with other genetic alterations.
LKB1 serves as a prognostic biomarker that influences treatment regimens. The signaling pathways regulated by LKB1 include AMPK, ARKs (AMP-activated protein kinases), MARKs (microtubule-associated serine/threonine-protein kinase family members), SIKs (serinethreonine-inactive kinase-like proteins), NUAKs (nucleoside diphosphate kinase type 2 homologues) and SNRKs. Depending on these downstream pathways, LKB1-AMPK or LKB1-ARK signaling can either enhance or inhibit tumor progression mediated by LKB1.
Hypermethylation of the LKB1 promoter is associated with tumorigenesis, while genomic alterations such as deletions, rearrangements, and splicing in the LKB1 gene lead to truncated proteins. The catalytic activity of LKB1 depends on pseudokinases STRAD and MO25; mutations in these proteins impair the function of LKB1-STRAD-MO25.
LKB1-STRAD-MO25 promotes tumorigenesis by increasing NADPH levels, thereby protecting cancer cells from ROS-mediated damage. Additionally, it enhances autophagy, resulting in chemotherapeutic resistance and enabling epithelial-mesenchymal transition (EMT) and invasion.
The LKB1-AMPK-mTOR pathway shields tumor cells from anoikis, a type of cell death that occurs when detached from the extracellular matrix. Disruption strategies for LKB1 activity involve blocking its kinase activity, nucleocytoplasmic shuttling, or STRAD binding.
Drugs such as metformin and AICAR act as AMPK agonists and represent potential therapeutic interventions targeting LKB1-AMPK signaling. Other treatments like erlotinib, bevacizumab (an antiangiogenic drug), PARP inhibitors, ERK inhibitors, and biguanides exhibit cytotoxic effects in cells deficient in LKB1.
The authors emphasize the need to explore context-specific roles of LKB1 and its regulation due to its paradoxical functions. This research provides a rationale for targeting LKB1 in cancer treatments, highlighting the importance of developing specific inhibitors that could selectively antagonize this kinase’s activities.
