Bepaling van het pro-apoptotisch Ca2+ profiel van kankercellen.

Pro- and anti-apoptotic proteins of the Bcl-2-family can modulate the activity of the inositol 1,4,5-trisphosphate receptor (IP3R) and therefore affect the endoplasmic reticulum (ER) Ca2+ homeostasis and its role in apoptosis. Moreover, the anti-cancer BH3-mimetic drug, ABT-737, binds to the hydrophobic groove of Bcl-2 and displaces pro-apoptotic BH3-only proteins from Bcl-2. ABT-737 by itself does not induce cell death in healthy cells, but instead enhances the apoptotic effects of death signals in cancer cells. In this study, we wish to investigate the role of IP3R/Bcl-2-protein complexes and Ca2+ signalling in a variety of cancer cell models. We anticipate provoking pro-apoptotic Ca2+ signalling in cancer cells through antagonistic peptides acting on the BH4 domain of Bcl-2 and interfering with IP3R/Bcl-2 complexes. First, we will characterize the pathophysiological IP3R/Bcl-2-family member interactome in a variety of cancer cells, including lymphoma, myeloma, lung and bladder cancer. Second, we will develop inhibitory IP3R-derived cellpermeable peptides to block the effect of anti-apoptotic Bcl-2-family members on the IP3R. Eventually, we will examine the pro-apoptotic Ca2+-signalling activity of IP3R-peptides as anti-proliferative agents in cancer cells and in an in vivo bladder tumour model, as synergistic tools for chemotherapeutic agents, including ABT-737 or for photodynamic therapy.

Trefwoorden:Cancer cells