Cryptobiosis, ageing and cancer: yin-yang balancing of signalling networks
Z. Huang, A. Tunnacliffe
Institute of Biotechnology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QT, UK
On experiencing a persistent, severe and unavoidable stress, a cell or
an organism will either establish a new equilibrium and continue to
exist, or perish if it fails to do so. To overcome such unfavourable
conditions, some organisms can tip the delicate balance to survival by
entering cryptobiosis, a quiescent state in which metabolism
essentially comes to a reversible standstill. The most well-known
cryptobiosis is anhydrobiosis, which enables certain organisms to
survive in the absence of water. Such an adaptation is in essence an
evasion of death, or suspended animation, after which normally
intolerable damage is either reparable or preventable. As a survival
strategy in nature anhydrobiosis involves morphological, physiological
and biochemical responses to desiccation. The complex cascade of
molecular events comprising the desiccation response can be
characterised at three levels: signal transduction, gene activation and
biochemical modulation. We have shown that even desiccation-sensitive
human cells are capable of responding to desiccation stress via MAPK
activation and induction of genes including those encoding zinc finger
transcription factors such as EGR1 and SNAI1. However, there is still
little information on how life forms achieve anhydrobiosis, and whether
and how such strategies can be conferred on non-anhydrobiotes. In
contrast, there is a vast body of literature on ageing and cancer
research. Ageing is also a type of adaptation to intrinsic as well as
external stresses, although the balance slowly tips irreversibly to one
end, i.e. from incremental accumulation of tolerable damage to ultimate
death. On the other hand, tumorigenesis tips the life and death balance
of cells towards prolonged life at the cellular level, despite the
paradoxical fact that the proliferation of such cells may eventually
cause the death of the organism as a whole. On molecular levels, all
these phenomena, i.e. cryptobiosis, ageing and tumorigenesis, involve
coordinated regulation of complex signalling networks, including
protein phosphorylation, activation or suppression of transcription
factors, and gene induction. Some pathways such as those involving
MAPKs and apoptosis are known to be instigated in response to
desiccation, ageing and carcinogens. Although further investigations
are needed to compare the well established signalling pathways such as
IGF, PI3K, NF-kB, SIRT, TOR, RB and p53 in their response to
cryptobiotic, ageing and carcinogenic stimuli, we consider it highly
likely that the balancing of signalling networks, rather than
individual pathways themselves, plays a critical role in the life and
death decisions at either cellular or organismal level. We further
examine the possibility of pharmacological intervention at critical
regulation steps of the complex signalling networks for the induction
of cryptobiosis and longevity and the prevention of cancer. In summary,
we propose life or death is a matter of balancing response networks at
molecular, cellular, organismal and even population levels and by
temporo-spatial control of key signalling nodes. Understanding the
common strategies, i.e. yin-yang regulation between intrinsic and
external factors, may provide an insight into anhydrobiotic
engineering, rejuvenation research and cancer treatment.
Key words:
ageing, anhydrobiosis, cancer, cell signalling, cryptobiosis
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