Unveiling the Double Edged Sword: The Dual Role of LKB1 in Cancer Suppression and Promotion

Mutations in serine-threonine kinase 11 (STK11) and liver kinase B1 (LKB1) are known to contribute to disease progression in Peutz-Jeghers syndrome, a condition which may eventually lead to cancer. Research indicates that the inhibition of LKB1 can result in tumor formation within animal models, whereas its overexpression has been shown to reduce microvessel density and cell proliferation while also decreasing tumor burden, thus positioning LKB1 as a tumor suppressor. However, conflicting evidence suggests that LKB1 may promote tumorigenesis by enhancing ROS scavenging, DNA repair mechanisms, and autophagy processes. This review article in the Genes & Diseases journal explores these dual roles of LKB1 signaling pathways, along with insights into the biochemical regulation of its activity and potential therapeutic applications.

Studies have identified somatic mutations in LKB1 alongside structural variants, amplifications, deletions, and other genetic alterations across various cancer types. These mutations often synergize with other existing gene changes to influence disease progression. Additionally, researchers have found that LKB1 mutations serve as prognostic biomarkers that can inform treatment strategies.

LKB1 influences tumor behavior through its substrates such as AMPK, ARKs, MARKs, SIKs, NUAKs, and SNRKs which either promote or suppress tumorigenesis depending on the downstream signaling pathways. For instance, LKB1-AMPK and LKB1-ARK signals can enhance or inhibit tumor growth based on their specific roles in cell physiology.

Genomic alterations of the LKB1 gene including deletions, rearrangements, and splicing events result in truncated proteins that alter its function. Furthermore, hypermethylation at the promoter region is linked to tumorigenesis. The catalytic activity of LKB1 depends on two pseudokinases: STRAD and MO25. Mutations within these proteins disrupt the functional interaction between LKB1-STRAD-MO25 complexes.

The activation of LKB1-STRAD-MO25 contributes to tumorigenesis in several ways, including increased NADPH levels which safeguard cancer cells from oxidative stress damage and enhance autophagy that leads to resistance against chemotherapy. This pathway also supports the epithelial-mesenchymal transition (EMT) process and cell invasion.

The LKB1-AMPK-mTOR signaling network plays a critical role in protecting tumor cells from anoikis, or programmed death triggered by loss of attachment to extracellular matrices. Potential strategies for inhibiting LKB1 activity include targeting kinase inhibition, nucleocytoplasmic shuttling, and STRAD binding sites.

Existing therapeutic interventions such as AMPK agonists like metformin and AICAR could potentially target the LKB1-AMPK signaling pathway. Additionally, cytotoxic drugs like erlotinib, metformin, bevacizumab, PARP inhibitors, ERK inhibitors, and biguanides have shown efficacy in cells deficient in LKB1.

The review concludes by highlighting the necessity of understanding context-specific roles of LKB1 within tumors and how its regulation may vary. It underscores that despite its paradoxical function in cancer biology, targeting LKB1 remains a promising therapeutic avenue. The development of specific inhibitors for LKB1 is suggested to selectively antagonize tumor-promoting signaling pathways without affecting essential physiological functions.