A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

Abstract

The 5'-AMP-activated protein kinase (AMPK) is a master regulator of cellular homeostasis. Despite AMPK's known function in physiology, its role in pathological processes such as prostate cancer is enigmatic. However, emerging evidence is now beginning to decode the paradoxical role of AMPK in cancer and, therefore, inform clinicians if - and how - AMPK could be therapeutically targeted. Spatiotemporal regulation of AMPK complexes could be one of the mechanisms that governs this kinase's role in cancer. We hypothesize that different upstream stimuli will activate select subcellular AMPK complexes. This hypothesis is supported by the distinct subcellular locations of the various AMPK subunits. Each of these unique AMPK complexes regulates discrete downstream processes that can be tumour suppressive or oncogenic. AMPK's final biological output is then determined by the weighted net function of these downstream signalling events, influenced by additional prostate-specific signalling.

Figure 1. Compartmentalized signaling

A, Example of compartmentalized signaling. In Scenario 1, a particular signaling complex is activated at a specific location (Location 1). At Location 1 are the parts needed to generate certain effects (A, B, C) that are also known to be regulated by the described active complex. Thus, when the active complex is at this site (Location 1), the associated downstream processes are regulated to produce effects A, B and C. Processes regulated by the active complex but located elsewhere, such as at Location 2 that could produce effects C and Y, will not be altered in this scenario. In contrast, when the complex is activated at Location 2 and not 1 such as in Scenario 2, then only effects C and Y are produced and not effects A and B. In Scenario 3, the complex is activated everywhere and hence, all known processes controlled by the active complex will be regulated, producing a broad range of effects (A, B, C, Y). B, Regarding AMPK-mediated cellular effects, there are different AMPK complexes located throughout the cell (ex. cytoplasmic versus nuclear). Depending on which of these complexes is activated (could be more than one), the net effect AMPK has on a cell will be the summation of the actions of all of the activated subcellular populations of AMPK and their associated downstream effector processes.

Figure 2. Upstream stimuli determine the differential regulation/activation of AMPK-mediated downstream effects

A, Depending on the particular upstream cue (ex. energy stress (Scenario 1) or phosphorylation by an upstream kinase (Scenario 2)), different subpopulations of AMPK can be activated (or inactivated). The net phenotypic effect of each type of AMPK activation will be the summation of all the regulated downstream pathways, shifting the balance between oncogenic and tumor suppressive AMPK signaling. In Scenario 1, all downstream AMPK targets (both oncogenic and tumor suppressive) are activated. Here, the tumor suppressive functions could dominate. In Scenario 2, there is a more selective activation of AMPK complexes that favor the induction of oncogenic downstream processes. B, The type of upstream stimuli and thus manner in which cellular AMPK complexes are activated is likely influenced by both the location of upstream cues and AMPK complexes, which can be influenced by amongst other aspects the subunit composition, as well as the duration of signal. In this regard, in Scenario 1, a persistent energetic stress such as high AMP (or ADP) levels would be able to activate the majority of AMPK complexes. In contrast, an upstream kinase with a more restricted location such as CaMKK2 (Scenario 2) could only phosphorylate/activate local AMPK complexes, perhaps for a limited duration. This would lead to a restricted set of downstream processes that AMPK could regulate.

Figure 3. Proposed regulation of AMPK in prostate cancer

AMPK can be activated by multiple posttranslational modifications as well as energetic stress (ex. high AMP or ADP levels). In the prostate, the dominant upstream kinase of AMPK is CAMKK2, a calcium-dependent kinase whose expression is directly controlled by AR signaling. In contrast, AMPK can be inactivated by upstream phosphatases that, to date, are still ill-defined in the prostate. Further, inhibitory phosphorylation events caused by other kinases have been described but it is unclear if these modifications occur in prostate cancer. Additionally, high levels of ATP are known to inhibit AMPK. However, the inhibition of ATP may be overridden when CAMKK2 is highly expressed.