"LKB1 is a master kinase"
What a great subheader in a paper last year by Reuben Shaw (journal link below).
Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers.
Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS). However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC).
Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase. Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.
Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day.
Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention. I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves.
It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis. This process represents the export of energy from hepatocytes to the organism in the form of glucose. In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level.
Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes.
What is interesting on several levels is:
- Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer
- Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer
Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex:
Source: University of Dundee
Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available. These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research.
Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail.
Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654
Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071