Cellular responses to metabolic stress. A study on the role of mitochondria in the crosstalk between cell metabolism and survival signaling

<p>Metabolic imbalance is associated with increased risk of several diseases, including
cancer. Metabolism affects or is affected by virtually all other cellular processes,
which is not surprising considering their conserved role throughout evolution.
Mitochondria are important sensors of the intracellular metabolic environment and
play a major role in bioenergetics and survival signaling in mammalian cells.
Accordingly, these cell organelles have been implicated in the development of cancer,
which includes changes in cellular metabolism and cell death signaling.</p><p>Metabolic reprogramming in cancer cells increases cell growth and proliferation.
This entails greater nutrient uptake which is metabolized to provide energy and
intermediates for cell constituents. This reprogramming has generally been
associated with increased therapeutic resistance, but may also prove to be utilized in
metabolic targeted therapies. Major signaling networks that are involved in tumor
growth and metabolic reprogramming are PI3K/Akt/mTOR signaling pathways often
found mutated in cancer cells. Activation of this pathway results in high glucose
dependency and aggressive tumors. On the other hand, the activation of a lowenergy-
responsive AMP-activated protein kinase (AMPK) signaling pathway leads to
growth inhibition. Both of these signaling pathways may regulate or be regulated by
mitochondrial functions, which has been the basis of this Ph.D study.</p><p>The aim of this work was to investigate interactions between cell metabolism and
signalling that affect mitochondrial function under conditions of energetic and
metabolic stress. In order to reflect different contexts of mitochondrial regulation, we
studied these mechanisms in both metabolically restricted cancer cells, as well as
metabolically flexible primary rat hepatocytes.</p><p>We found that leukemia cells that have mutations in the PI3K/Akt/mTOR signaling
pathway (Jurkat) were more susceptible to glucose deprivation and agents that
challenge this metabolism (such as palmitic acid). Alternatively, leukemia cells that use more oxidative phosphorylation for their metabolism (HL-60) showed increased
resistance to glucose deprivation, but higher susceptibility to agents interfering with
their mitochondrial function (such as resazurin and AICAR). Metabolically flexible
primary cells (hepatocytes) were found to adjust their metabolism in response to
agents that induce increased metabolic stress (TTA). Interestingly, this involved the
nutrient sensing mTOR signaling pathway, which may play a role in regulating cell
size, whereas we found no indications of hyperplasia (no neoplastic growth of the
liver).</p><p>These studies support the growing understanding that metabolic characterization of
cancer cells and its effects on and by mutations in cell signalling pathways, not only
gives us a better understanding of tumour biology, but may also provide additional
treatment targets and strategies in cancer therapy. It is thus a possibility that
treatments targeted to metabolism cause cell stress and death in metabolically
compromised cancer cells, while more benign reversible stress responses may occur
in normal cells.</p