Arias, F. | Search bioRxiv

bioRxiv2018

Radiopotentiation of Enzalutamide over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

While radiotherapy is the first line of treatment for prostate cancer, androgen blockade therapies are demonstrating significant survival benefit as monotherapies. As androgen blockade can cause cell death by apoptosis, it is likely that androgen blockade will potentiate the cytotoxic activities of radiotherapy. Here we tested the potential synergistic effects of these two treatments over two human metastatic prostate cancer cells by real time growth monitoring (RTCA), androgen-sensitive LNCaP cells and androgen-resistant PC-3. Both cell lines were highly resistant to high doses of radiotherapy. A pre-treatment of LNCaP cells with IC50 concentrations of enzalutamide significantly sensitized them to radiotherapy through enhanced apoptosis. In contrast, enzalutamide resistant PC-3 cells were not sensitized to radiotherapy by androgen blockade. These results provide evidence that the enzalutamide/radiotherapy combination could maximize therapeutic responses in patients with enzalutamide-sensitive prostate cancer.

cancer biology↗

bioRxiv2017

The Centrosome Controls the Number and Spatial Distribution of Microtubules by Negatively Regulating Alternative MTOCs

In this work, we have investigated in mammalian cells how microtubule nucleation at centrosome and Golgi apparatus are coordinated, using genetic ablation of three {gamma}-TuRC binding proteins -AKAP450, Pericentrin and CDK5Rap2- and the PLK4 inhibitor centrinone. We show that centrosomal microtubule nucleation is independent of Golgi activity whereas the converse is not true: nucleation on the Golgi negatively correlates with the number of centrosomes. In addition, depleting AKAP450 in cells lacking centrioles, that abolishes Golgi nucleation activity, leads to microtubule nucleation from numerous cytoplasmic Golgi-unbound acentriolar structures containing Pericentrin, CDK5Rap2 and y-tubulin. Strikingly, centrosome-less cells display twice higher microtubule density than normal cells, suggesting that the centrosome controls the spatial distribution of microtubules, not only by nucleating them, but also by acting as a negative regulator of alternative MTOCs. Collectively, the data reveals a hierarchical control of microtubule nucleation, with the centrosome regulating this process in a more complex manner than usually thought. It also unveils mechanisms that could help understanding MT network reorganization during cell differentiation.

cell biology↗