AMPKα Isoform Suppression in Bladder Cancer Promotes Tumorigenesis

AMPK functions to maintain homeostasis in the cell by altering cellular metabolism in response to low nutrients. AMPK activation has been demonstrated to reduce tumor growth through negatively regulating mTOR in multiple cancers. Furthermore, AMPK activation is reduced in hepatocellular carcinoma and breast cancer and this is due to a reduction in the protein level of the AMPKa2 isoform. Since it has been shown that mTOR is activated in bladder cancer, it was hypothesized that bladder cancer growth is a result of activated mTOR which is due to a reduction in the activity level of AMPKa and/or a reduction in the protein levels of. AMPKa activation was found to be suppressed in bladder cancer and this was a result from the suppression of both AMPKa1 and AMPKa2 protein (Chapter 2). Given the finding that AMPKa is suppressed in bladder cancer, the effect of AMPKa2 knock-down in bladder cancer cells was assessed. Knockdown of AMPKa2 in bladder cancer cells resulted in increased cell proliferation and increased xenograft tumor growth due to a reduction in p27 protein which was a result of an increase in SKP2, the E3 ubiquitin ligase responsible for p27 degradation. Furthermore, genetic deletion of AMPKa2 in a chemical model of bladder cancer supported this mechanism (Chapter 3). In order to determine the mechanism for AMPKa suppression, inflammatory mediated mechanisms were assessed (Chapter 4). It was found that macrophages, in particular TNFa from macrophages, are responsible for the suppression of AMPKa. Furthermore, it was determined that inflammatory mediated microRNAs (Chapter 5) and/or inflammatory mediated ubiquitin ligases (Chapter 6) may be partially responsible for the suppression of AMPKa. Together these results demonstrate the importance of AMPKa in bladder cancer and demonstrate a potential mechanism for its suppression in bladder cancer