Biology Reference
In-Depth Information
AMPK as a Therapeutic Target
LKB1 directly targets AMPKs and is associated with cell cycle regulation, micro-
tubule dynamics, cell polarity and differentiation, and not unexpectedly attributed
with activation of AMPKs and regulation of metabolic functions. Given the tumour
suppressor function of LKB1, AMPK provides a metabolic link with pathogenesis
of cancer besides acting as an active nexus with signalling systems related to apop-
tosis and cell cycle regulator genes. Upon activation by LKB1, AMPKs liaise with
many tumour suppressor genes and interact with several signalling systems such as
p53, BRCA, Wnt/β-catenin and mTOR, among others. Therefore AMPKs have been
viewed as a legitimate therapeutic target and have been the focus of much attention
and investigation. Many agents that activate AMPKs have been identified and some
studied in great detail. Several erudite reviews have been written on the subject, but a
restricted purview is provided here.
AMPK functions through the FOXO family transcription factors which participate
in the regulation of cell proliferation, apoptosis. FOXO transcription factor isoforms
FOXO1, FOXO3 and FOXO4 are phosphorylated by PI3K/Akt and sequestered to
the cytoplasm and prevented from inducing cell cycle arrest and apoptosis. FOXO-
dependent induction of cell cycle arrest and apoptosis are suppressed in response to
growth factors. AMPK also phosphorylates FOXO but at regulatory sites different from
those phosphorylated by Akt. FOXO activation by AMPK leads to cell cycle arrest
and apoptosis (Salih and Brunet, 2008). They are functionally downregulated in many
forms of cancer and might thus lead to cell survival and tumorigenesis. Some isoforms
may be associated with angiogenesis, so by implication in tumour progression and
prognosis. An overall assessment would be that FOXOs are tumour suppressors, but
the inevitable diversity of the transcription function of individual FOXOs is reflected
in their being ascribed a role in the maintenance of CSCs such as leukaemic stem cells.
AICAR (5-aminoimidazole-4-carboxamide
1-D-ribonucleoside)
The AICAR is an AMPK activator. Inhibition of AMPK has led to the downregula-
tion of p53 and p21 and attendant promotion of cell proliferation. Loss of AMPK
function also leads to enhanced cell motility, whereas in contrast AMPK activation
by AICAR produced the opposite effect (Zhou et al., 2009). Oestrogen/ER and p53
background signalling might be relevant in AICAR-mediated activation of AMPK
(El-Masry et al., 2012). Activation of p53 by AICAR seems to engage the ATM and
mTOR pathways. Inhibitors of ATM kinase suppress the activation and so do also
mTOR inhibitors (Zajkowicz and Rusin, 2011). Obviously ATM pathway is opera-
tional in this experimental system. As discussed already, the ATM pathway regulates
many signalling systems that culminate in DNA repair, apoptosis or cell survival. It
involves the downstream checkpoint kinases Chk1 and Chk2, and p53 and BRCA1
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