Type

Journal Article

Authors

Jochen H M Prehn
Heinrich J Huber
Douglas R Green
Suzanne Hector
Elaine W Kay
Frank Murray
Deborah A McNamara
Joan Kehoe
Karen Boland
Deborah Ryan
and 5 others

Subjects

Medicine & Nursing

Topics
colorectal cancer crc bcl2 family bcl2 responses bh3 only proteins model analysis systems analysis state of the art cancer cells

Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy. (2013)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Heinrich J Huber, Douglas R Green, Suzanne Hector, Elaine W Kay, Frank Murray, Deborah A McNamara, Joan Kehoe, Karen Boland, Deborah Ryan and 5 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Suzanne Hector
Royal College of Surgeons in Ireland
Total Publications: 13
 
4
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157
 
5
F E Murray
Royal College of Surgeons in Ireland
 
6
Deborah A McNamara
Royal College of Surgeons in Ireland
Total Publications: 17
 
7
K C Boland
Royal College of Surgeons in Ireland
Total Publications: 8
 
8
Deborah Ryan
Royal College of Surgeons in Ireland
Total Publications: 4