New insights into the Bcl2 family: from biophysics to function

Microtubule-targeting agents (MTAs) are standard of care for a number of human cancers. Including breast and lung cancer. Their mode of action includes prolonged arrest of the cell cycle by interfering with a tubular apparatus (spindle) that leads to the activation of a control mechanism known as the spindle assembly checkpoint (SAC) preventing cell division (mitosis). Cells stalled in mitosis usually can undergo two different fates, either cell death, or, alternatively, checkpoint adaptation (slippage). The latter occurs when levels of a particular protein, CyclinB, fall below a critical level, due protein degradation. This often correlates with a concomitant reduction of mediators of cell death that belong to the BCL2 family. This leads to premature exit from mitosis and escape from cell death, generating cells that have duplicated their genome but failed to divide. Such cells are well known to become genetically instable due to unfaithful segregation of chromosomes leading to chromosomal instability (CIN). The fate of such chromosomally instable (cancer) cells is usually regulated by the tumor suppressor p53, the gene most frequently mutated in human cancer, and its activation can either result in cell death, by in this context poorly defined molecular mechanisms (mitotic catastrophe), or cellular senescence (a form of irreversible cell cycle arrest). In the absence of p53, such cells can escape these control mechanisms, leading to the creation and expansion of aneuploidy clones that form the basis of cancer-evolution, progressive disease and ultimately also drug-resistance. The aim of this proposal is to (i) define the mechanisms controlling activity of Bcl-2 family proteins relevant in mitotic and post-mitotic cell death and to (ii) interrogate the contribution of BCL2-regulated cell death in and out of mitosis as a barrier against aneuploidy and cancer.

Within this international research project we were exploring the role of individual proteins of the BCL2 family in controlling cell death after experiencing different types of errors before, during or after cell division, e.g. in response to checkpoint kinase inhibitors or microtubule poissons, drugs currently tested or already used in the clinics to treat cancer patients. Thereby, we identified the molecular mechanisms how these anti-cancer drugs promte cell death and were able to define a central role for mitochondria in this process, together with colleagues at the University of Cologne, DE. Together with colleagues at the University of Bern, in Switzerland, we were able to assign a previously unrecognized tumor-promoting role to one particularly understudied protein of the BCL2 family, called BOK and with colleagues in Freiburg, DE, we could elucidate critical protein-protein interactions that control mitochondria-regulated cell death. Together, these findings will be helpful to understand the molecular basis of drug-induced cancer cell death and this should help to optimize current treatment strategies and reduce potential side effects of these drugs. Moreover, a followup research proposal has been developed and submitted to the German Research Funding Agency, DFG, aiming to continue these collaborative efforts.