Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic beta-catenin activation.

PURPOSE: Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone. METHODS: We assessed the activation states of beta-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy. RESULTS: We found two distinct patterns of nuclear accumulation of activated beta-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type beta-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type beta-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type beta-catenin activation. CONCLUSIONS: The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.

Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer.

BACKGROUND: The ubiquitin-proteasome pathway is important in regulating protein signaling pathways that are involved in tumorigenesis. beta-transducin repeat-containing proteins (beta-TrCP) are components of the ubiquitin ligase complex targeting beta-catenin and IkappaBalpha for proteasomal degradation and are thus a negative regulator of Wnt/beta-catenin signaling and a positive regulator of NF-kappaB signaling. We analyzed expression of beta-TrCP in colorectal cancers and its association with types of beta-catenin subcellular localization, an indirect measure of activation. METHODS: Levels of beta-TrCP1 mRNA and protein were measured by quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively, in samples of tumor and normal tissues from 45 patients with colorectal cancer. Types of beta-catenin activation (diffuse or invasion edge) and NF-kappaB activation were examined by immunohistochemistry. Apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay. All statistical tests were two-sided. RESULTS: Compared with the beta-TrCP1 levels in normal tissues, 25 (56%) of 45 tumors had increased beta-TrCP1 mRNA and protein levels. Of the 22 (49%) tumors with beta-catenin activation, 12 had the diffuse type (i.e., nuclear accumulation throughout the tumor) and 10 had the invasion edge type (i.e., nuclear accumulation predominantly in the tumor cells that formed the invasion edge). Increased beta-TrCP1 levels were statistically significantly associated with beta-catenin activation (P =.023) and decreased apoptosis (P =.035). beta-TrCP accumulated in the nuclei of tumor cells that contained increased levels of beta-TrCP1 mRNA and the active form of NF-kappaB. Higher levels of beta-TrCP1 mRNA were detected in primary tumors of patients who had metastases (0.960 arbitrary units, 95% confidence interval = 0.878 to 1.042) than in the tumors of patients who did not (0.722 arbitrary units, 95% confidence interval = 0.600 to 0.844; P =.016). CONCLUSION: In colorectal cancer, increased expression of beta-TrCP1 is associated with activation of both beta-catenin and NF-kappaB, suggesting that the integration of these signaling pathways by increased beta-TrCP expression may contribute to an inhibition of apoptosis and tumor metastasis.