A multi-disciplinary approach to exploit pro-apoptotic Ca2+ signaling as a novel anti-cancer strategy.

Intracellular Ca2+ signals mediated by the inositol 1,4,5-trisphosphate receptor (IP3R) controls a plethora of cellular processes, including apoptosis. Recently, we discovered that Bc1-2, through its BH4 domain, is inhibits IP3R activity in normal cells, preventing excessive Ca2+ signalling in cancer cells. First, we will characterize the molecular determinants and functional regulation of IP3R-mediated Ca2+ signalling by Bcl-2-family members in normal cells and in a number of cancer cells, including a collection of BH3-profiled lymphoma cells. Furthermore, we will apply cell-permeable IP3R-mimetic peptides targeting the BH4 domain of Bcl-2 for reversing the inhibitory effect of anti-apoptotic Bcl-2 proteins on IP3Rs, in order to induce proapoptotic Ca2+ signalling in cancer cells. Finally, we aim to design a pharmacophore model for the development and screening of peptidomimetic small molecules that target the BH4 domain of Bcl-2 and interfere with IP3R/Bcl-2-protein complexes.

Keywords:Peptidomimetics, Apoptosis, Intracellular Ca2+-release channels, Protein complexes, Bcl-2 proteins, Lymphomas, Endoplasmic reticulum, Calcium signaling

Disciplines:Biochemistry and metabolism, Systems biology, Medical biochemistry and metabolism, Physiology, Medicinal and biomolecular chemistry, Molecular and cell biology, Plant biology, Biophysics