Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5

Cancers

Felicitas Pardow¹  JoséLuis Villanueva-Cañas¹  RoniH. G. Wright¹  KatherineE. Pickup¹  José Carbonell-Caballero¹  Miguel Beato¹  Antonios Lioutas¹ 

[1] Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain;

关键词: breast cancer;    proliferation;    oncospheres;    cell–cell communication;    cytoskeleton;    motility;    recurrence;    cancer stem cell (CSC), metastasis;    3D cell cultures;    EMT;   

DOI  :  10.3390/cancers11091337

来源: DOAJ

【 摘 要 】

The growth of cancer cells as oncospheres in three-dimensional (3D) culture provides a robust cell model for understanding cancer progression, as well as for early drug discovery and validation. We have previously described a novel pathway in breast cancer cells, whereby ADP (Adenosine diphosphate)-ribose derived from hydrolysis of poly (ADP-Ribose) and pyrophosphate (PPi) are converted to ATP, catalysed by the enzyme NUDT5 (nucleotide diphosphate hydrolase type 5). Overexpression of the NUDT5 gene in breast and other cancer types is associated with poor prognosis, increased risk of recurrence and metastasis. In order to understand the role of NUDT5 in cancer cell growth, we performed phenotypic and global expression analysis in breast cancer cells grown as oncospheres. Comparison of two-dimensional (2D) versus 3D cancer cell cultures from different tissues of origin suggest that NUDT5 increases the aggressiveness of the disease via the modulation of several key driver genes, including ubiquitin specific peptidase 22 (USP22), RAB35B, focadhesin (FOCAD) and prostagladin E synthase (PTGES). NUDT5 functions as a master regulator of key oncogenic pathways and of genes involved in cell adhesion, cancer stem cell (CSC) maintenance and epithelial to mesenchyme transition (EMT). Inhibiting the enzymatic activities of NUDT5 prevents oncosphere formation and precludes the activation of cancer driver genes. These findings highlight NUDT5 as an upstream regulator of tumour drivers and may provide a biomarker for cancer stratification, as well as a novel target for drug discovery for combinatorial drug regimens for the treatment of aggressive cancer types and metastasis.

【 授权许可】

Unknown