A team headed by Xavier Salvatella, ICREA researcher from the Institute for Research in Biomedicine (IRB Barcelona) at the Barcelona Science Park, has discovered a new avenue through which to attack prostrate cancer cells that have developed drug-resistance. Published in the journal Structure, part of the Cell group, the study has involved Angel R. Nebreda’s lab and the Experimental Bioinformatics Lab, both at IRB Barcelona, and also the University of Barcelona.  

In most cases, prostate cancer is cured by surgical removal of the tumour and/or by radiotherapy. However, 20% of patients will need treatment to remove tumour cells but this treatment ceases to be effective after two or three years and the cancer develops further. Once this stage of the disease has been reached, there is no cure.

The survival and proliferation of prostate tumour cells calls for highly active androgen receptor protein. The drug used to remove tumour cells interferes with this protein by binding to a specific region of the receptor and blocking its activity. “Over time, the protein accumulates alterations and mutates, and there comes a point where it is futile to target this region with drugs because, in fact, it is no longer there,” says Salvatella.

The Molecular Biophysics Laboratory, headed by Salvatella, studies the tridimensional structure and atomic movements of the androgen receptor, with the aim to find new binding sites. It has been known for some years that the protein has a small region, spanning only 20 amino acids, that is important for tumour cell survival. 

The study now describes for the first time that this region—usually without a structure and therefore a priori disregarded as a drug target—has a helix shape. on—usually without a structure and therefore a priori disregarded as a drug target—has a helix shape. Upon gaining this helix—it is not known how the helix occurs—, another protein, called TFIIF, binds to it. The study reveals that this interaction stimulates the activity of the androgen receptor and, consequently, facilitates the survival and multiplication of tumour cells.

► More information: IRB Barcelona website [+]

► Reference article:

Eva De Mol, Elzbieta Szulc, Claudio Di Sanza, Paula Martínez-Cristóbal, Carlos W. Bertoncini, R. Bryn Fenwick, Marta Frigolé-Vivas, Marianela Masín, Irene Hunter, Víctor Buzón, Isabelle Brun-Heath, Jesús García, Gianni De Fabritiis, Eva Estébanez-Perpiñá, Iain J. McEwan, Ángel R. Nebreda, and Xavier Salvatella. “Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators”. Structure (2017). DOI: http://dx.doi.org/10.1016/j.str.2017.11.007