Identification of the Ca2+-transport systems and mechanisms contributing to the cell death of cancer B cells upon disruption of IP3R/Bcl-2 complexes

An important part of Bcl-2’s function in cancer cells is to prevent the occurrence of “toxic” Ca2+- release events from the endoplasmic reticulum (ER), the main intracellular Ca2+ store. These Ca2+- release events are mediated by the IP3 receptor, a major class of intracellular Ca2+-release channels in close contact with the mitochondria, the main apoptosis executioner organelle. Hence, inhibiting Bcl-2’s function at the level of the ER using a peptide tool that targets its BH4 domain is able to strip Bcl-2 proteins from IP3 receptor channels, causing their de-inhibition, provoking intracellular Ca2+ overload and subsequent cell death in a subset of B-cell cancer cells. However, the role of the mitochondria, the Ca2+-flux pathways and underlying mechanisms that contribute to the cell death in these cells upon targeting the BH4 domain of Bcl-2 remain poorly understood. The aim of this project is elucidate these detailed molecular mechanisms, including the Ca2+-transport systems responsible for causing the flooding of the mitochondria with Ca2+, the tethering of the ER to the mitochondria and the subsequent consequences of these events. These molecular studies will result in a better understanding how antagonizing Bcl-2 at the ER Ca2+ store results in cancer cell death. These insights will be instrumental for the future development of anti-cancer strategies based on these tools.