Every year, millions of people are diagnosed with cancer, and cancer is one of the leading causes of premature death. Cancer is described as a group of diseases defined by uncontrolled cellular growth. Here, many patients diagnosed with cancer will develop complications in addition to the cancer disease itself. One of these complications is the development of metabolic dysfunction, including insulin resistance. As the development of metabolic dysfunction in patients increases the risk of cancer reoccurrence and death, there is a necessity for treating such conditions. There is currently limited molecular knowledge
regarding the pathology of cancer-induced metabolic dysfunction. Thus, the primary aim of the current PhD project was to investigate the mechanisms underlying metabolic dysfunction in cancer.
Using a pre-clinical model of cancer, the Lewis lung carcinoma model, it was showed that especially muscle with an oxidative phenotype developed insulin resistance compared to muscle with a glycolytic phenotype, that did not develop insulin resistance. This was associated with the development of “selective insulin resistance”. More specifically, parts of the insulin signaling cascade were abrogated in the oxidative muscle, where several phosphorylation-sites on the protein TBC1D4 were reduced. Additionally, it was showed that subunits of the metabolic stress-sensor, AMP-activated protein kinase (AMPK), were
upregulated in skeletal muscle of patients with cancer-induced muscle loss, known as cachexia (non-small cell lung carcinoma). Lacking functional AMPK in muscle during tumordevelopment in mice aggravated cancer-induced metabolic dysfunction, where treatment with an AMPK activator alleviated insulin intolerance in tumor-bearing mice. In skeletal muscle, cancer led to changes in proteins involved in glucose metabolism in an AMPKdependent manner. This included the phosphorylation of TBC1D4 and the increase in the protein expression of pyruvate dehydrogenase. Thus, these data suggest that muscle AMPK has a protective role in cancer-induced metabolic dysfunction.
Collectively, the current project provides a greater molecular understanding of the alterations of skeletal muscle seen in the context of cancer in the lung. Furthermore, data of the current PhD project suggest that AMPK may be a possible pharmacological target in treatment of cancer-associated metabolic dysfunction.