Is 5´-AMP-Activated Protein Kinase Both Jekyll and Hyde in Bladder Cancer?

The 5´-AMP-activated protein kinase (AMPK) is a key regulator of cellular metabolism and energy homeostasis in mammalian tissues. Metabolic adaptation is a critical step in ensuring cell survival during metabolic stress. Because of its critical role in the regulation of glucose homeostasis and carbohydrate, lipid, and protein metabolism, AMPK is involved in many human diseases, including cancers. Although AMPK signaling was originally characterized as a tumor-suppressive signaling pathway, several lines of evidence suggest that AMPK plays a much broader role and cannot simply be defined as either an oncogenic regulator or tumor suppressor. Notably, several recent studies demonstrated that the antitumorigenic effects of many indirect AMPK activators, such as metformin, do not depend on AMPK. Conversely, activation of AMPK induces the progression of cancers, emphasizing its oncogenic effect. Bladder cancer can be divided into two groups: non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). The molecular mechanisms underlying these two types of cancer are distinct: NMIBC is associated with activation of the Ras pathway, whereas MIBC is characterized by loss of major tumor suppressors. Importantly, both pathways are connected to the mammalian target of rapamycin (mTOR) pathway. In addition, our recent metabolomic findings suggest that β-oxidation of fatty acids is an important factor in the development of bladder cancer. Both mTOR and β-oxidation are tightly associated with the AMPK pathway. Here, I summarize and discuss the recent findings on the two distinct roles of AMPK in cancer, as well as the relationship between bladder cancer and AMPK.