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.
- MeSH
- buněčné linie MeSH
- chromatografie kapalinová MeSH
- Fanconiho anemie metabolismus MeSH
- glykolýza MeSH
- lidé MeSH
- metabolické sítě a dráhy * MeSH
- metabolomika metody MeSH
- oprava DNA MeSH
- oxidativní fosforylace MeSH
- proteomika metody MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A growing body of evidence supports the notion that cancer resistance is driven by a small subset of cancer stem cells (CSC), responsible for tumor initiation, growth, and metastasis. Both CSC and chemoresistant cancer cells may share common qualities to activate a series of self-defense mechanisms against chemotherapeutic drugs. Here, we aimed to identify proteins in chemoresistant triple-negative breast cancer (TNBC) cells and corresponding CSC-like spheroid cells that may contribute to their resistance. We have identified several candidate proteins representing the subfamilies of DNA damage response (DDR) system, the ATP-binding cassette, and the 26S proteasome degradation machinery. We have also demonstrated that both cell types exhibit enhanced DDR when compared to corresponding parental counterparts, and identified RAD50 as one of the major contributors in the resistance phenotype. Finally, we have provided evidence that depleting or blocking RAD50 within the Mre11-Rad50-NBS1 (MRN) complex resensitizes CSC and chemoresistant TNBC cells to chemotherapeutic drugs.
- MeSH
- chemorezistence účinky léků genetika MeSH
- cisplatina aplikace a dávkování MeSH
- cyklofosfamid aplikace a dávkování MeSH
- DNA vazebné proteiny genetika MeSH
- doxorubicin aplikace a dávkování MeSH
- enzymy opravy DNA genetika MeSH
- homologní protein MRE11 genetika MeSH
- hydrolasy působící na anhydridy kyselin genetika MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- nádorové kmenové buňky účinky léků metabolismus MeSH
- poškození DNA účinky léků MeSH
- přežití po terapii bez příznaků nemoci MeSH
- proteiny buněčného cyklu genetika MeSH
- triple-negativní karcinom prsu farmakoterapie genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- glukoneogeneze účinky léků MeSH
- glukosa analýza metabolismus MeSH
- glykogen metabolismus MeSH
- glykogenolýza * MeSH
- glykolýza * MeSH
- hypoxie buňky MeSH
- indoly farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky metabolismus MeSH
- nádorové mikroprostředí MeSH
- oxidativní fosforylace MeSH
- propanoly farmakologie MeSH
- triple-negativní karcinom prsu metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cancer cells are known to reprogram their metabolism to adapt to adverse conditions dictated by tumor growth and microenvironment. A subtype of cancer cells with stem-like properties, known as cancer stem cells (CSC), is thought to be responsible for tumor recurrence. In this study, we demonstrated that CSC and chemoresistant cells derived from triple negative breast cancer cells display an enrichment of up- and downregulated proteins from metabolic pathways that suggests their dependence on mitochondria for survival. Here, we selected antibiotics, in particular - linezolid, inhibiting translation of mitoribosomes and inducing mitochondrial dysfunction. We provided the first in vivo evidence demonstrating that linezolid suppressed tumor growth rate, accompanied by increased autophagy. In addition, our results revealed that bactericidal antibiotics used in combination with autophagy blocker decrease tumor growth. This study puts mitochondria in a spotlight for cancer therapy and places antibiotics as effective agents for eliminating CSC and resistant cells.
- MeSH
- chemorezistence * účinky léků MeSH
- lidé MeSH
- linezolid aplikace a dávkování farmakologie MeSH
- metabolické sítě a dráhy * účinky léků MeSH
- mitochondrie účinky léků metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky účinky léků metabolismus MeSH
- nádorové mikroprostředí účinky léků MeSH
- proliferace buněk účinky léků MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- transplantace nádorů MeSH
- triple-negativní karcinom prsu farmakoterapie metabolismus patologie MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
