Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and a high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. In order to elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia inducible factor-1α (HIF-1α). Using western blotting, we confirmed that HIF-1α is significantly upregulated in the heart, while there were no changes in its regulatory proteins, PHD2 and VHL. PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL, and subsequent destruction by the proteasome complex. We examined blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared to control animals. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response not only in the heart but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes that occur during cancer cachexia.
- hypoxia inducible factor
- cancer cachexia
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology