PDF file - 237K, Supplementary Table 1: Translation of protein interactions into Ordinary Differential Equations. Supplementary Table 2: Pseudo-reactions for degradation and degradation rates as used in the model. Supplementary Table 3: Pseudo-reactions and kinetics for inhibition of BH3 only proteins and effectors BAK and BAX by anti-apoptotic proteins. Supplementary Table 4: BAK and BAX activation and BAK inhibition by VDAC2. Supplementary Table 5: Effector homo-oligomerization. Supplementary Table 6: Modeling apoptosis sensitizers ABT-737 and ApoG2. Supplementary Table 7 Two tBID chimeras were modeled to reproduce the findings of Llambi et al. Supplementary Table 8: BCL2 protein quantification of CRC cell lines. Supplementary Table 9: BCL2 protein quantification of CRC patient samples.
ARTICLE ABSTRACT
Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519–28. ©2012 AACR.
