AMP-activated protein kinase and energy balance in breast cancer

Abstract

Cancer growth and metastasis depends on the availability of energy. Energy-sensing systems are critical in maintaining a balance between the energy supply and utilization of energy for tumor growth. A central regulator in this process is AMP-activated protein kinase (AMPK). In times of energy deficit, AMPK is allosterically modified by the binding of increased levels of AMP and ADP, making it a target of specific AMPK kinases (AMPKKs). AMPK signaling prompts cells to produce energy at the expense of growth and motility, opposing the actions of insulin and growth factors. Increasing AMPK activity may thus prevent the proliferation and metastasis of tumor cells. Activated AMPK also suppresses aromatase, which lowers estrogen formation and prevents breast cancer growth. Biguanides can be used to activate AMPK, but AMPK activity is modified by many different interacting factors; understanding these factors is important in order to control the abnormal growth processes that lead to breast cancer neoplasia. Fatty acids, estrogens, androgens, adipokines, and another energy sensor, sirtuin-1, alter the phosphorylation and activation of AMPK. Isoforms of AMPK differ among tissues and may serve specific functions. Targeting AMPK regulatory processes at points other than the upstream AMPKKs may provide additional approaches for prevention of breast cancer neoplasia, growth, and metastasis.

Keywords: AMP-dependent protein kinase; Breast cancer; biguanides.

Figure 1

Domain structure of typical mammalian AMPK. AMPK complexes are heterotrimers composed of α-, β- and γ-subunits in a 1:1:1 ratio. The β-subunit carboxy-terminal domain (β-CTD) forms the core of the AMPK complex, binding to the α-CTD sequence in the α-subunit and the β-binding sequence in the amino terminus of the γ-subunit (green). The β-subunit also contains a carbohydrate-binding module (CBM) that is a binding site for glycogen (purple). The catalytic α-subunit contains conventional serine/threonine kinase domains with a threonine residue (Thr172) that is phosphorylated by upstream kinases (red). The kinase domain is followed by an auto-inhibitory domain (AID; blue) that has a negative effect on kinase activity. The AID is connected to the α-CTD by a less well conserved linker (orange). A flexible serine-threonine-rich loop (ST loop) within the α-CTD can be phosphorylated by Akt. The γ-subunit contains variable NH2-terminal regions followed by the short β-subunit binding sequence, then four tandem repeats of cystathionine β-synthase (CBS) motifs that act in pairs to form the binding sites for adenine nucleotides in mammalian AMPK (yellow). There is one binding site between CBS1 and CBS2 and two binding sites between CBS3 and CBS4. Four CBS domains are paired to form two Bateman domains.

Figure 2

Activation of AMPK by endogenous hormonal and metabolic factors. Pathways that activate AMPK are shown in green and pathways that inhibit AMPK are shown in purple. Within the AMPK heterotrimer, the AMP/ADP binding site(s) are shown on the γ-subunit (triangle); the phosphorylation site (Thr172) is shown on the α-subunit (oval). Downstream targets of AMPK are shown in blue and red, leading to stimulation of energy storing pathways (blue) and inhibition of energy utilization pathways (red), as well as inhibition of aromatase.