OPG is regulated by beta-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer.
OBJECTIVE
Resistance to apoptosis is a hallmark of cancer and correlates with aggressiveness of tumors and poor prognosis. The Wnt/beta-catenin pathway plays a pivotal role in the genesis of colorectal cancer by mechanisms not fully elucidated yet. Previous studies have linked regulation of osteoprotegerin (OPG) in bone to Wnt/beta-catenin signaling. As OPG also serves as a decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we hypothesized that OPG might play a role in mediating resistance to apoptosis in colorectal cancer cells.


METHODS
Expression analysis and functional studies in human colorectal cancer cell lines and determination of expression in primary tumors and sera from patients with colorectal cancer.


RESULTS
We found production of OPG in colorectal cancer cells to be regulated by beta-catenin/Tcf-4. Addition of exogenous OPG to colorectal cancer cells caused resistance to TRAIL. Similarly, accumulation of OPG in medium of cultivated cells caused resistance to TRAIL, and this could be reverted by removal of OPG. Furthermore, OPG levels were significantly increased in serum of patients with advanced disease.


CONCLUSIONS
We conclude that the Wnt/beta-catenin pathway contributes to carcinogenesis and cancer cell survival by driving expression of OPG. Expression of the survival factor OPG might provide colorectal cancer cells with an essential growth advantage and contribute to cell invasion and metastasis. Inhibition of OPG expression might offer a new therapeutic approach for the treatment of patients with colorectal tumors overexpressing OPG and make these tumors sensitive to TRAIL-induced apoptosis.
De Toni
Enrico N
EN
Department of Medicine II, University of Munich, Munich, Germany.
Thieme
Susanne E
SE
Herbst
Andreas
A
Behrens
Andrea
A
Stieber
Petra
P
Jung
Andreas
A
Blum
Helmut
H
Göke
Burkhard
B
Kolligs
Frank T
FT
D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D015179:Colorectal Neoplasms; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D053244:Osteoprotegerin; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051176:beta Catenin