Abstract
Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.
| Original language | English |
|---|---|
| Article number | 881297 |
| Journal | Frontiers in Cell and Developmental Biology |
| Volume | 10 |
| DOIs | |
| Publication status | Published - Apr 28 2022 |
Bibliographical note
Funding Information:Cancer Research Society, The Canadian Cancer Society Diane Campbell designated research fund (grant #706202). Natural Sciences and Engineering Research Council of Canada.
Funding Information:
The importance of glycolysis is not only through energy production, but glycolytic intermediates are important for many anabolic processes such as nucleotide synthesis and generating ROS scavengers (; ). Cancer cells characteristically show increased utilization of glucose by glycolysis and a shift from OXPHOS to glycolysis to support their growth and division (). This idea has recently been questioned as OXPHOS was shown to still be utilized for energy production in some cancers (). OXPHOS is supported by lactate import and utilization through the TCA cycle, while glucose is used to support glycolysis and the pentose phosphate pathway (PPP) shunt to produce ROS scavenger NADPH. NADPH manages ROS stress and is important in generating ribose-5-phosphate for nucleotide biosynthesis (; ) (,).
Publisher Copyright:
Copyright © 2022 Bourouh and Marignani.
ASJC Scopus Subject Areas
- Developmental Biology
- Cell Biology
PubMed: MeSH publication types
- Journal Article
- Review
