Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

Abstract

The precise role of 5′AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. While it is well established that activation of this energy sensor inhibits the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a “conditional” tumor suppressor and “contextual” oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation and provides an overview of the most relevant data available on AMPK activation and AMPK activating drugs in human studies.

The Role of AMPK in Metabolic Changes in Pancreatic Cancer Cells through High Protein Diet

“…Additionally, inhibition of unchecked mTORC1 activity and de novo lipogenesis, results in applying metabolic tumor-suppressor role of the AMPK. It is of worth mentioning that both mTORC1 activity and de novo lipogenesis are required during G1-S and G2-M phases [3]. It is proved that there is an inverse relationship between de novo FA synthesis concomitant and phosphorylation of its major target ACC1, prior to cytokinesis initiation.…”

“…The mediation would take place under the close interaction between energy regulators and cancer pathogeneses. The presence of variety of subunits in AMPK implies the particularity of the tissues which can further contribute to growth of tumor cell and its independent reproduction [3].…”

“…Thus, AMPK has been linked to the regulation of tumorigenesis. AMPK includes three upstream kinases namely the tumor suppressor LKB1, CaMKK β (Ca 2+ /calmodulin-dependent protein kinase β) and TAK1 (TGF-β-activated kinase-1) [3].Regardless of the energy status of the cells, AMPK is stimulated during energy stress formed by LKB1 but CaMKK2 activate by increased amount of intercellular Ca 2+ [3].…”

“…Hence, AMPK can potentially be considered as a tumor suppressor due to proximity to the established aforementioned tumor suppressors. AMPK has vital roles in several tumor types and can act as pro-tumorigenic or anti-tumorigenic in cancerous tumors [3] (Fig. 1).…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…Despite the many connections between AMPK and cancer cell proliferation, mutations in the AMPK β1 subunit are not common in cancers (Forbes et al ., 2015) and recent studies have suggested that inhibition of AMPK may make cancer cells more sensitive to apoptosis (Jeon et al ., 2012; Shackelford et al ., 2013; Zadra et al ., 2015). Thus far, only one study has examined the effects of germline deletion of AMPK in a mouse model of tumorigenesis where the authors observed that deletion of the AMPK α1 isoform promoted B‐cell lymphoma when crossed to c‐Myc transgenic mice (Faubert et al ., 2013).…”