Antagonism between salicylate and the cAMP signal controls yeast cell survival and growth recovery from quiescence

Authors:

Maurizio D. Baroni1, Sonia Colombo2 and Enzo Martegani2

doi: 10.15698/mic2018.07.640
Volume 5, pp. 344 to 356, published 26/03/2018.

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Affiliations:

1 Dipartimento di Biologia, Università di Padova, 35133 Padova, Italy.

2 Dipartimento di Biotecnologie e Bioscienze, Università Milano Bicocca, 20126 Milano, Italy.

Keywords: 

Salicylate, cyclic AMP, cellular growth, cell death, yeast, NSAIDs

Corresponding Author(s):

Maurizio David Baroni, University of Padua, Department of Biology, Via Ugo Bassi 58/b, 35131 Padova, Italy; mauriziodavide.baroni@unipd.it Enzo Martegani, University of Milano-Bicocca, Department of Biotechnology and Bioscience, Buildings U3-U4, Piazza della Scienza 2-4, 20126 Milano, Italy; enzo.martegani@unimib.it

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Maurizio D. Baroni, Sonia Colombo and Enzo Martegani (2018). Antagonism between Salicylate and the cAMP signal controls yeast cell survival and growth recovery from quiescence. Microbial Cell: in press.

© 2018 Baroni et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Aspirin and its main metabolite salicylate are promising molecules in preventing cancer and metabolic diseases. S. cerevisiae cells have been used to study some of their effects: (i) salicylate induces the reversible inhibition of both glucose transport and the biosyntheses of glucose-derived sugar phosphates, (ii) Aspirin/salicylate causes apoptosis associated with superoxide radical accumulation or early cell necrosis in MnSOD-deficient cells growing in ethanol or in glucose, respectively. So, treatment with (acetyl)-salicylic acid can alter the yeast metabolism and is associated with cell death. We describe here the dramatic effects of salicylate on cellular control of the exit from a quiescence state. The growth recovery of long-term stationary phase cells was strongly inhibited in the presence of salicylate, to a degree proportional to the drug concentration. At high salicylate concentration, growth reactivation was completely repressed and associated with a dramatic loss of cell viability. Strikingly, both of these phenotypes were fully suppressed by increasing the cAMP signal without any variation of the exponential growth rate. Upon nutrient exhaustion, salicylate induced a premature lethal cell cycle arrest in the budded-G2/M phase that cannot be suppressed by PKA activation. We discuss how the dramatic antagonism between cAMP and salicylate could be conserved and impinge common targets in yeast and humans. Targeting quiescence of cancer cells with stem-like properties and their growth recovery from dormancy are major challenges in cancer therapy. If mechanisms underlying cAMP-salicylate antagonism will be defined in our model, this might have significant therapeutic implications.