The Role of the Tumor Suppressor Kinase LKB1 in Xenobiotic Metabolism
Kohnz, Rebecca Ann
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The liver kinase-B1 (LKB1) is a serine/threonine kinase that has numerous roles in human disease. LKB1 was originally identified as a tumor suppressor kinase that, when inactivated, is responsible for the human inherited disorder Peutz-Jeghers syndrome which is characterized by benign gastric polyposis and increased cancer predisposition. More recently, inactivating LKB1 somatic mutations in humans have been found in 15-35% of non-small cell lung carcinomas and in 20% of cervical carcinomas. LKB1 functions as a master kinase upstream of 14 different substrates kinases and these substrates have critical roles in cell growth, polarity, and metabolism. Previous studies show that in specialized metabolic tissues such as the liver LKB1 and its downstream substrate AMPK control cholesterol, lipid, and glucose metabolism. However, LKB1's role in other biological processes in the mammalian liver is poorly understood. To identify pathways deregulated upon loss of LKB1 signaling a microarray screen was employed using mice with an inducible liver-specific deletion of Lkb1. Unexpectedly, one of the most prominently deregulated pathways upon hepatic LKB1 loss is the xenobiotic metabolism pathway. Xenobiotic metabolism occurs primarily in the liver and serves to remove endogenous and exogenous compounds from the organism. Mice lacking hepatic LKB1 have reduced expression of many phase I xenobiotic metabolism genes, collectively known as the cytochrome P450 family (CYP). In particular, expression of CYP2E1, an important mediator of drug interactions, was markedly reduced upon LKB1 loss. LKB1-deficient livers exhibit a decreased response to hepatocarcinogens compared to wild-type controls. In addition, mice lacking hepatic LKB1 are refractory to all stages of liver carcinogenesis promoted by repeated high-dose administration of the hepatocarcinogen carbon tetrachloride. Thus, it appears that LKB1 is an important regulator of xenobiotic metabolism and attenuation of this pathway could be useful in mediating toxicity of drugs or other exogenous compounds.