Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas

Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurre...

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Published in:Clinical cancer research 2008-09, Vol.14 (18), p.5810-5818
Main Authors: SINICROPE, Frank A, REGO, Rafaela L, OKUMURA, Kenji, FOSTER, Nathan R, O'CONNELL, Michael J, SARGENT, Daniel J, WINDSCHITL, Harold E
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis
Apoptosis Regulatory Proteins - metabolism
Bcl-2-Like Protein 11
BH3 Interacting Domain Death Agonist Protein - metabolism
Bim
Biological and medical sciences
Biomarkers, Tumor - analysis
colon cancer
Colonic Neoplasms - diagnosis
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Fluorouracil - therapeutic use
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Medical sciences
Membrane Proteins - metabolism
Noxa
Pharmacology. Drug treatments
Prognosis
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Puma
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary:Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates. Experimental Design: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil–based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays ( n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates. Results: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS ( P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS ( P = 0.0034) and OS ( P = 0.0011). Conclusions: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil–based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-07-5202