Echinococcus Sirtuins: expression and link to metformin-treatment

COCCIMIGLIO, MAGALÍ; LOOS, JULIA A.; CUMINO, ANDREA C.

Mar del Plata

Congreso; lLXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

AMPK and Sirtuin 1 are involved in a positive amplification loop which acts to initiate autophagy in nutrient deprivation conditions. We have reported that during Echinococcus pharmacological treatment with metformin were promoted the AMPK activation, glycogenolysis, homolactic fermentation and autophagy (through the transcripcinal activity of FoxO), attacking the glucose-dependent metabolism and thus, the parasite survival. Since metformin is well-established to activate both AMPK and sirtuin 1, and sirtuin 1 could modify the acetylation status of FoxO, we infer the presence and activity of sirtuin class I in Echinococcus. Also, we described the presence and levels of differential expression of the different sirtuins and to link them with functions that would have in relation to the metabolic characteristics of the parasite stages. Sirtuins form a superfamily of conserved NAD+-dependent protein deacylases with roles in metabolism and cell survival. Of the seven types of sirtuins (Sirt1-7) present in metazoans, Echinococcus sp. express Sirt1-3 and Sirt5-7, but lack Sirt4 in accordance with the chromosomal instability and high rate of cell division that shown the cestode. Echinococcus sirtuins have a conserved structure of the catalytic domain (composed of a NAD+-binding Rossmann fold domain and a smaller Zn2+-binding domain with four conserved Cys residues) as do those of other helminthes, albeit large insertions are identified in their sequences, probably involved in protein-protein interactions. Our results showed that Eg-sirt1 and Eg- sirt 2 genes have a high expression level in larval forms, and that Eg- sirt3 and Eg- sirt6 has a low expression level in metacestodes. This issue is accordance to the Warburg effect promotion of this larval form, a strategy acquired by Echinococcus germinal cells to cope with the high demand of energy and intermediate metabolites under limited oxygen supply, which could confer cells susceptibility to metformin, as it has been described for tumor cells.