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2018 ; 9
(ä): 714
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How Tumor Cells Choose Between Epithelial-Mesenchymal Transition and Autophagy to
Resist Stress-Therapeutic Implications
#MMPMID30013478
Marcucci F
; Rumio C
Front Pharmacol
2018[]; 9
(ä): 714
PMID30013478
show ga
Tumor cells undergo epithelial-mesenchymal transition (EMT) or macroautophagy
(hereafter autophagy) in response to stressors from the microenvironment. EMT
ensues when stressors act on tumor cells in the presence of nutrient sufficiency,
and mechanistic target of rapamycin (mTOR) appears to be the crucial signaling
node for EMT induction. Autophagy, on the other hand, is induced in the presence
of nutrient deprivation and/or stressors from the microenvironment with 5'
adenosine monophosphate-activated protein kinase (AMPK) playing an important, but
not exclusive role, in autophagy induction. Importantly, mTOR and EMT on one
hand, and AMPK and autophagy on the other hand, negatively regulate each other.
Such regulation occurs at different levels and suggests that, in many instances,
these two stress responses are mutually exclusive. Nevertheless, EMT and
autophagy are able to interconvert and we suggest that this may depend on
spatiotemporal changes in the tumor microenvironment and/or on duration/intensity
of the stressor signal(s). Eventually, we propose a three-pronged therapeutic
approach aimed at targeting these three major tumor cell populations. First,
cytotoxic drugs that act on differentiated and proliferating tumor cells and
which, per se, may promote induction of EMT or autophagy in surviving tumor
cells. Second, inhibitors of mTOR in order to prevent EMT induction. Third
inducers of autophagic cell death (autosis) in order to deplete tumor cells that
are constitutively in an autophagic state or are induced to enter an autophagic
state in response to antitumor therapy.