TY - JOUR

T1 - Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells

AU - Abad, Etna

AU - Samino, Sara

AU - Grodzicki, Robert L.

AU - Pagano, Giovanni

AU - Trifuoggi, Marco

AU - Graifer, Dmitry

AU - Potesil, David

AU - Zdrahal, Zbynek

AU - Yanes, Oscar

AU - Lyakhovich, Alex

N1 - Funding Information: This work was supported by grants from the Instituto de Salud Carlos III: PI17/02087 ( AL ), The proteomic part of the work was supported by the project CEITEC 2020 ( LQ1601 ) from The Ministry of Education, Youth and Sports of the Czech Republic (MEYS CR). DP and ZZ thank for support of Czech Science Foundation project (no. P206/12/G151 ). CIISB research infrastructure project LM2015043 funded by MEYS CR is gratefully acknowledged for the financial support of the LC-MS/MS measurements at the Proteomic Core Facility. Publisher Copyright: © 2020 Elsevier B.V. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4/10

Y1 - 2021/4/10

N2 - Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.

AB - Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.

KW - Cancer predisposition

KW - de novo purine biosynthesis

KW - Fanconi anemia

KW - Fumarate

KW - Metabolic reprogramming

KW - Purinosome

UR - http://www.scopus.com/inward/record.url?scp=85099198211&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2020.12.010

DO - 10.1016/j.canlet.2020.12.010

M3 - Article

C2 - 33316348

AN - SCOPUS:85099198211

VL - 503

SP - 185

EP - 196

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -