Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cells Vitality by Modulating Autophagy/Mitophagy and ROS

Federica Barreca
,
Michele Aventaggiato
ORCID logo ,
Laura Vitiello
ORCID logo ,
Luigi Sansone
ORCID logo ,
Matteo Antonio Russo
,
Antonello Mai
ORCID logo ,
Sergio Valente
ORCID logo ,
Marco Tafani
* ORCID logo
Version 1 : Received: 30 May 2023 / Approved: 30 May 2023 / Online: 30 May 2023 (12:51:57 CEST)

A peer-reviewed article of this Preprint also exists.

Barreca, F.; Aventaggiato, M.; Vitiello, L.; Sansone, L.; Russo, M.A.; Mai, A.; Valente, S.; Tafani, M. SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cell Vitality by Modulating Autophagy/Mitophagy and ROS. Antioxidants 2023, 12, 1635. Barreca, F.; Aventaggiato, M.; Vitiello, L.; Sansone, L.; Russo, M.A.; Mai, A.; Valente, S.; Tafani, M. SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cell Vitality by Modulating Autophagy/Mitophagy and ROS. Antioxidants 2023, 12, 1635.

Abstract

Cancer cells show an increased glutamine consumption. The glutaminase (GLS) enzyme controls a limiting step in the glutamine catabolism. Breast tumors, especially the triple negative subtype, have a high expression of GLS. Our recent study demonstrated that GLS activity and ammonia production are inhibited by Sirtuin 5 (SIRT5). We have developed MC3138, a selective SIRT5 activator. Treatment with MC3138 mimicked the deacetylation effect mediated by SIRT5 overexpression. Moreover, GLS activity is regulated by inorganic phosphate (Pi). Considering the interconnected role of GLS, SIRT5 and Pi for cancer growth, our hypothesis is that activation of SIRT5 and reduction of Pi could represent a valid anti-tumoral strategy. Treating cells with MC3138 and lanthanum acetate, a Pi chelator, decreased cell viability and clonogenicity. We also observed a modulation of LC3 and ULK1 with MC3138 and lanthanum acetate. Interestingly, inhibition of mitophagy marker BNIP3 was observed only in the presence of MC3138. Such autophagy and mitophagy modulation was accompanied by an increase of cytosolic and mitochondrial reactive oxygen species (ROS). In conclusion, our results show how SIRT5 activation and/or Pi binding can represent a valid strategy to inhibit cell proliferation by reducing glutamine metabolism and mitophagy leading to a deleterious accumulation of ROS.

Keywords

Autophagy; Mitophagy; ROS; Sirtuins; Glutamine; Glutaminase; Hypoxia

Subject

Biology and Life Sciences, Biology and Biotechnology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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