Polyamines reshape protein phosphorylation to guide key cellular fate decisions

Polyamines are small molecules naturally present in all cells and are critical in guiding cellular decisions, whereas an alteration in the abundance of these metabolites is invariably observed in pathological scenarios such as cancer or aging. Despite decades of research, the mechanisms through which polyamines control cellular decisions has remained obscure.

A collaborative study recently published in the prestigious journal Nature and led by scientists in CIC bioGUNE, reports the discovery of a mechanism that reformulates our understanding about the actions of polyamines in health and disease. Using an integrated approach that combined molecular simulations, biochemical and structural analyses, proteomics, and cellular assays, the scientific team identified that these metabolites alter the phosphoproteomic landscape, which has important repercussions for protein function. They focus on proteins that take part in the control of alternative splicing, a process that alters that repertoire of RNAs and proteins in our cells. The research team could pinpoint the recognition mode of polyamines on target proteins and demonstrate that this process can be disrupted or potentiated through genetic or pharmacological means. With hundreds of proteins exhibiting potential polyamine-binding motifs, this study opens the door for a renewed perception of polyamine-regulated cellular responses.

Polyamines are overproduced in cancer, and their loss is associated to the process of ageing. In turn, inhibiting polyamine metabolism through pharmacological approaches has been evaluated in different cancers, and it is currently employed as a therapeutic strategy in neuroblastoma. Conversely, dietary polyamine supplementation is posed as an innovative strategy to counteract ageing. The findings of Zabala, Pujana and colleagues could contribute to elucidate the effectors of polyamines in these processes, thus helping in the design of next-generation dietary and pharmacological interventions.

The work was led by Dr. Arkaitz Carracedo, Ikerbasque Research Professor, head of the Cancer Cell Signaling and Metabolism Laboratory at CIC bioGUNE (member of BRTA) and group leader in CIBERONC, with Dr. Amaia Zabala-Letona and Dr. Mikel Pujana-Vaquerizo as co-first authors.

This body of work represents an international collaboration involving more than 25 institutions, including CIC bioGUNE, CIBERONC and CIBERehd, Ikerbasque, the Centre for Genomic Regulation (CRG), the Spanish National Cancer Research Centre (CNIO), Memorial Sloan Kettering Cancer Center (USA), the Children's Hospital of Philadelphia and the University of Pennsylvania (USA), the University of Zurich and University Children's Hospital Zurich (Switzerland), the Vall d'Hebron Institute of Oncology (VHIO), the Universitat Autònoma de Barcelona (UAB), and the Universitat Pompeu Fabra (UPF).

The research was funded through competitive calls from Spanish and European research programs, including national agencies, CIBER biomedical networks, the Spanish Association against Cancer (AECC), regional funding bodies, and institutional support from participating centers, as well as additional international funding for cancer and basic biomedical research.