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

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.

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

“…Before that, salicylates from willow bark were widely used in folk medicine. Aspirin, which quickly metabolizes to salicylate in vivo, has lifespan-increasing effects on model organisms, including mice (Strong et al, 2008), but seems to inhibit growth in yeast (Baroni et al, 2018;Carmona-Gutierrez et al, 2018;Madeo et al, 1997).…”

A Versatile Transcription Factor Biosensor System Responsive to Multiple Aromatic and Indole Inducers

“…P CCW12 was engineered to be salicylate-responsive by introducing two copies of the cmeO operator sequence 11 bp downstream of the TATA box consensus sequence TATA(A/T)A(A/T)(A/G) 43 found at −133–125 nt relative to the transcription start site, thereby generating P CCW12O and the sensor strain ( Figure 2 A). Due to the toxicity of salicylate to S. cerevisiae , 44 , 45 all experiments were conducted at a lower yeast culture dilution factor and were measured after 8 h. GFP fluorescence outputs of the control and sensor strains measured by flow cytometry showed a marked drop in fluorescence upon inserting cmeO , which in turn increased by adding increasing concentrations of salicylate to the culture media, reaching up to ∼4.3-fold induction in 2.5 mM salicylate ( Figure 2 B). This data shows that, in a manner similar to our E. coli genetic circuit, CmeR functions as a transcription repressor in S. cerevisiae , and is inducible by salicylate.…”

In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase

“…Cells were grown at 30 °C with shaking (200 rpm) into liquid synthetic defined media (SD) containing 2% glucose, 6.7 g/l YNB w/o amino acids (ForMedium™, UK) and the proper selective drop-out CSM (Complete Synthetic Medium, ForMedium™), with the exceptions of snf1 or tps1 strain grown in SD + 5% glucose or 2% galactose, respectively. Growth was monitored either by measuring the absorbance ad 600 nm (OD 600 ), or by counting the cell number with a Coulter Counter (Beckman-Coulter Z2) after a mild sonication [ 9 ].…”

“…This appears to be consistent with the interaction between HCA and the signalling pathways of RAS2 or SCH9. Indeed, in optimal growth conditions, the loss of either gene poorly affects µ [43,44], while these regulators are important for cell responses during physiological transitions, in particular involving nutrients, cellular quiescence or oxidative stresses [9,[44][45][46][47]. Consequently, HCA effects on metabolism were more directly investigated by measuring the oxygen consumption rate (OCR) of stationary phase cells, just before they started to age (day 0 CLS, see above) (Fig.…”

“…In MnSOD-deficient yeast cells aspirin/salicylate starve the mitochondria of acetyl-CoA, inducing cell death [ 8 ]. In WT yeast cells salicylate can alter the balance between cell quiescence, death and proliferation as a function of metabolic signals [ 9 ]. Hydroxycitric acid, usually extracted from Garcinia cambogia [ 10 ], is widely used as a diet supplement for weight reduction [ 11 ].…”