LKB1 Kinase as a Tumor Suppressor

Posted by Van M

News Article:
Drug Week editors (October 20, 2006). Cancer Therapy; Lung cancer cell invasion suppressed by a kinase.

Primary Scientific Article:
Upadhyay, S. et. al (2006). LKB1/STK11 Suppresses Cyclooxygenase -2 Induction and Cellular invasion through PEA3 in Lung Cancer. Cancer Research Vol.66, pp. 7870-7879

Articles citing primary article:
Upadhyay, S. et. al ( 2007). Tap63y Regulates hOGG1 and Repair of Oxidative Damage in Cancer Cell Lines. Biochemical and Biophysical Research Communications Vol.356, pp. 823-828.

Zhang, S. et. al (2008).The Tumor Suppressor LKB1 Regulates Lung Cancer Cell Polarity by Mediating cdc42 Recruitment and Activity. Cancer Research Vol. 68, pp. 740-748.

Jiang, J. et. al (2007). E1AF Promotes Breast Cancer Cell Cycle Progression via Upregulation of Cyclin D3 Transcription. Biochemical and Biophysical Research Communications Vol.358, pp. 53-58.


This study was done to show how the inactivation of LKB1 kinase, led to Peutz- Jeghers syndrome, and invasion of lung cancer cells. The researchers knew that germ line mutations of LKB1 caused Peutz- Jeghers syndrome. PJS is an autosomal inherited disorder. PJS is characterized by intestinal hamartomas (polyps), oral mucocutaneous hyperpigmenation. The formation of hamartomas and tumors in PJS is caused by, the inactivation of the wild type LKB1 allele. The point of this research was to identify how the stabilization of PEA3 led to greater invasion of lung cancer.
In 2006, a group of researchers found a link between the suppression of cell invasion, by a kinase. The researchers are saying that the LKB1 kinase is a tumor suppressor in lung cancer. Tissues with mutations in LKB1, showed greater expression of PEA3 and cyclooxygenase-2, than wild type LKB1.The normal function of LKB1gene is to phosphorylate PEA3, targeting it for degradation by a proteosome. Once PEA3 is destroyed it can no longer activate the expression of COX-2. Over expression of COX-2 enhances the motility and invasiveness of the cell. When a mutated form of the LKB1 kinase in lung cancer loses its function, it no longer phosphorylates PEA3. Forced expressions of PEA3 cause the invasion of non- small cell lung cancer.
In this study, Upadhyay and colleagues investigated the association between LKB1, and PEA3. They removed the COOH- terminal from the full length LKB1. Deletion of the COOH- terminal reduced the ability of the cell to self activate. The terminal was used to screen the two hybrid cDNA from human prostate cells. Human prostate- derived ETS factor was identified. Similarities between PDEF and PEA3 were shown through a homology search. To test for the association between LKB1 and PEA3, PEA3 was cloned into a prey plasmid, and a yeast two hybrid analysis using the COOH terminal sub cloned into another plasmid. The ETS domain of PEA3 was shown to be necessary for its interaction with LKB1.
The article from drug week told us that LKB1 suppressed the induction of COX-2, through PEA3, but it did not tell how that happened. The primary research tells where these researchers can go next with this study. For example, they can go on to study the effects of nimesulide, and its inhibition of proliferation in non- small cell lung cancer. The primary research also mentioned the use of PEA3 along with COX-2, might prove to be a good therapeutic agent to treat cancers with mutations in LKB1. Knowing that the germ line mutation of LKB1 causes PJS, is there something that can be done, to ensure that it is never passed on to offspring? Also if there is no way to make sure PJS is not inherited, are there medications that can control the malignancies caused by PJS?