Cancer cells exhibit molecular changes that potentially could result in apoptosis; however, cancer cells often select for a block in apoptotic signaling that results in survival. BCL-2 family members function and control apoptotic signals in the mitochondria, and the authors probe the mechanism by which BCL-2 family members can be affected to overcome the proapoptotic signals. The work outlined in this manuscript takes a sweeping analysis of the BH3-containing family members and their expression in different lymphoma cell lines and correlates the mechanism of apoptotic block with sensitivity to chemotherapeutic agents.
The investigators draw from an array of knowledge about proteins in the BCL-2 family and their specific function in programmed cell death and apply this knowledge to classifying apoptotic block in lymphoma cell lines. Diffuse large B-cell lymphomas that represent the same class of disease but have heterogeneous mechanisms for overcoming apoptotic signals were used as a model in their studies. BH3 peptides were used to distinguish or profile three types of apoptotic block: a) inhibition of upstream activation of BH3-only proteins, b) loss of BAX and BAK so that the effector of apoptosis is lost, and c) expression of antiapoptotic proteins that prevent activation of BAX and BAK ("primed cancer cells"). Different classes of BH3 peptides were used to probe the models and predict the block in lymphoma cell lines that contained t(14;18) or did not. The different blocks were confirmed by analysis of BCL-2 proteins that were predicted by the BH3 peptide. Interestingly, their profiling predicted sensitivity to BCL-2 antagonism by the BH3 antagonist ABT-737. High abundance of BCL-2:BIM complex predicted sensitivity to ABT-737, and further characterization revealed that BCL-2 levels correlated with sensitivity. The investigators took this analysis beyond ABT-737 and treated the lymphoma cell lines with agents that have previously been shown to induce apoptosis through the mitochondrial pathway and confirmed that this model was predictive of relative chemotherapeutic sensitivity beyond inhibitors of BH3 domains.
In Brief
Predicting sensitivity and understanding resistance to chemotherapeutic agents in diseases that are biologically similar but molecularly heterogeneous is of critical importance. The investigators focused on diffuse large-cell lymphoma and were able to classify cell lines based upon their sensitivity to BH3 peptides into groups that had differences in apoptotic block. Although this work was done in cell lines, the authors’ findings not only confirmed their ability to profile at the molecular level but also put forth an explanation of why high BCL-2 levels may not uniformly provide protection against chemotherapeutic agents. BCL-2, from their model, would be proposed to be occupied in contrast to cell lines where BCL-2 was over-expressed and therefore largely unoccupied. Because BCL-2 is largely occupied, the cancer cell is felt to be primed for high sensitivity to chemotherapeutic agents. The data using conventional chemotherapeutic agents that use intrinsic apoptotic pathways support the idea that cells primed for cell death are more likely to respond whereas those with other types of blocks are not as likely to respond. The work presented within this manuscript suggests that profiling is possible and that sensitivity to ABT-737 can be predicted by BH3 profiling. More detailed analysis may allow us to learn whether classification will enable us to distinguish sensitivity to different chemotherapeutic agents.
Competing Interests
Dr. Petruzzelli indicated no relevant conflicts of interest.
