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

Key Points

  • 5′ AMP-activated protein kinase (AMPK) is a heterotrimer complex, that can exist in at least 12 different permutations, each of which can have different subcellular locations and activities

  • Diverse upstream signals regulate different AMPK subcellular complexes

  • AMPK was first identified as a master regulator of metabolism, but could have numerous roles beyond metabolism

  • AMPK can have context-dependent effects in cancer

  • CaMKK2 seems to be the dominant upstream AMPK kinase in the prostate

  • Most small molecule modulators of AMPK have known off-target effects

  • Given its ubiquitous expression and varied roles throughout the body, directly targeting AMPK could present numerous on-target side effects

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.

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Figure 1: Compartmentalized AMPK signalling.
Figure 2: Upstream stimuli determine the differential regulation/activation of AMPK-mediated downstream effects.
Figure 3: Proposed regulation of AMPK in prostate cancer.

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Acknowledgements

The authors gratefully acknowledge members of the Frigo laboratory for helpful discussions and critical reading of this manuscript. This work was supported by NIH grant R01CA184208, American Cancer Society grant RSG-16-084-01–TBE, Department of Defense/PCRP grant W81XWH-12-1-0204, and funding from the Golfers Against Cancer.

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A.S.K. and D.E.F. contributed equally to the manuscript. Both researched data for the manuscript, wrote the article, and edited the manuscript prior to submission.

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Correspondence to Daniel E. Frigo.

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D.E.F. declares a familial association with Essa Pharma. A.S.K. declares no competing interests.

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Khan, A., Frigo, D. A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer. Nat Rev Urol 14, 164–180 (2017). https://doi.org/10.1038/nrurol.2016.272

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