• Prostate cancer
• Cancer Stem Cells
• Sigma-1

Prostate cancer (PCa) is the second most frequent cancer in men worldwide. The clinical evolution of PCa is quite heterogeneous, ranging from indolent to very aggressive tumors that rapidly evolve in metastatic and castration resistant prostate cancer (CRPC). The factors that contribute to the heterogeneity and aggressive clinical behavior of PCa are not clear. The conventional therapies have proved to be inefficient with a high probability of tumor relapse and evolution in more severe forms. One of the underlying causes is the existence of a subpopulation of cells with stem-like properties, termed cancer stem cells (CSCs). CSCs play a role as tumorinitiating and tumor propagating cells. They are capable of continuous self-renewal and are able to generate more differentiated non-stem cancer cells. One of their hallmarks is the reprogramming of the cellular energy metabolism. This feature provides to CSCs the ability to respond to metabolic stress, adapt and survive.
Understanding the mechanisms sustaining CSC metabolism may identify relevant targets for therapeutic applications. In this context, the chaperon protein Sigma-1 represents an interesting target for CSC-directed approaches. Sigma-1 is localized at the mitochondria endoplasmic reticulum interface and controls many cellular processes, including Ca2+exchange, mitochondrial function and stress response.
Although the relevance of Sigma-1 in other diseases is well established, the potential role of Sigma-1 in cancer biology is just emerging.
In this project, we aimed at investigating the role of Sigma-1 in prostate cancer cells with different stem-like phenotype and tumorigenic potential. An additional aim wasto produce recombinant Sigma-1 protein to study binding to small molecule ligands
and protein-protein interactions for future mechanistic studies and design novel selective Sigma-1 inhibitors.
To achieve the first goal, androgen-receptor negative DU145 prostate cancer cells were cultured as bulk tumor cells or under conditions that enriched for stem-like tumor cells. Interestingly, we found that, after treatment with specific Sigma-1 inhibitors, proliferation of bulk tumor cells was only slightly affected. On the contrary, the ability to form tumor-spheres, a specific property of CSCs, was strongly reduced.
In parallel, we found that mitochondrial respiration was impaired after treatment with Sigma-1 ligands in cells growing in CSC selective conditions. These results suggest that inhibition of Sigma-1 has a major impact in the maintenance and expansion of the CSC subpopulation, likely by affecting mitochondrial respiration and function. Sigma-1 appears as a promising target for CSC eradication and novel specific inhibitors might be effective anticancer drugs.