ABSTRACT
To establish a nomogram for elderly patients with diffuse large B-cell lymphoma (DLBCL) based on nutritional and imaging features. The data of 221 elderly pretreatment DLBCL patients were retrospectively analyzed. All cases were randomly separated into the training group and validation group. A nomogram was built based on the results of multivariate analysis. A nomogram was established based on maximum standardized uptake value (SUVmax), geriatric nutritional risk index (GNRI), and lactate dehydrogenase. The concordance index (C-index) of the nomogram was 0.772 for the training group and 0.729 for the validation group, and similar results were found in the area under the curve (AUC). The calibration curve showed favorable consistency between prediction and real survival. The decision curve analysis (DCA) also showed that the nomogram had favorable clinical effectiveness. The new risk-stratification model divided patients into three groups with obvious survival. The C-index and AUCs for the new model were greater than those of IPI and NCCN-IPI. The DCA curve suggested that the new model had better clinical effectiveness than the IPI and NCCN-IPI. The nomogram prognostic model based on SUVmax and GNRI performed superior to NCCN-IPI and equal to IPI for risk stratification of elderly DLBCL patients.
ABSTRACT
Aberrant activation of the Wnt/ß-catenin pathway leads to the development of multiple cancers, including breast cancer. Development of therapeutic agents against this signaling pathway is an urgent need. In this study, we found that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) could inhibit Wnt/ß-catenin signaling mainly through targeting the low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed that CDDO-Me mediated the degradation of FZD7 in an LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and FZD7 and reduced the levels of phosphorylated Disheveled (DVL) 2 and active ß-catenin, resulting in the downregulation of Wnt target genes and several cancer stem cell (CSC) marker genes. In a murine xenograft bearing mouse mammary tumor virus (MMTV)-Wnt1-driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth and was accompanied by reduced expression of phosphorylated and total LRP6, phosphorylated and unphosphorylated DVL2, active ß-catenin, several Wnt target genes, and CSC marker genes. Collectively, the results of our study present that CDDO-Me is a potent Wnt/ß-catenin signaling inhibitor that may be a promising therapeutic agent against breast cancer. SIGNIFICANCE STATEMENT: Blocking the membrane receptor complex consisting of low-density lipoprotein receptor-related protein (LRP) 6 and Frizzled (FZD) 7 may help developing therapeutic approaches for cancers, including breast cancers. Our study indicates that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-methyl ester (CDDO-Me) can inhibit Wnt/ß-catenin signaling by inducing the ubiquitination and degradation of LRP6/FZD7 membrane receptor complex via a lysosomal pathway. We also found that the ectodomain of LRP6 is essential for CDDO-Me-induced FZD7 degradation. Defining CDDO-Me as a novel inhibitor of Wnt/ß-catenin signaling, our results provide insight into the mechanism of its anticancer activity.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/metabolism , Drug Delivery Systems/methods , Frizzled Receptors/metabolism , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Oleanolic Acid/analogs & derivatives , Animals , Breast Neoplasms/drug therapy , Dose-Response Relationship, Drug , Female , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Transgenic , Oleanolic Acid/administration & dosage , Random Allocation , Xenograft Model Antitumor Assays/methodsABSTRACT
BACKGROUND AND PURPOSE: Salinomycin is a well-known inhibitor of human cancer stem cells (CSCs). However, the molecular mechanism(s) by which salinomycin targets colorectal CSCs is poorly understood. Here, we have investigated underlying antitumour mechanisms of salinomycin in colorectal cancer cells and three tumour models. EXPERIMENTAL APPROACH: The inhibitory effect of salinomycin on the Wnt/ß-catenin pathway was analysed with the SuperTopFlash reporter system. The mRNA expression of Wnt target genes was evaluated with real-time PCR. Effects of salinomycin on ß-catenin/TCF4E interaction were examined using co-immunoprecipitation and an in vitro GST pull-down assay. Cell proliferation was determined by BrdU incorporation and soft agar colony formation assay. The stemness of the cells was assessed by sphere formation assay. Antitumour effects of salinomycin on colorectal cancers was evaluated with colorectal CSC xenografts, APCmin/+ transgenic mice, and patient-derived colorectal tumour xenografts. KEY RESULTS: Salinomycin blocked ß-catenin/TCF4E complex formation in colorectal cancer cells and in an in vitro GST pull-down assay, thus decreasing expression of Wnt target genes. Salinomycin also suppressed the transcriptional activity mediated by ß-catenin/LEF1 or ß-catenin/TCF4E complex and exhibited an inhibitory effect on the sphere formation, proliferation, and anchorage-independent growth of colorectal cancer cells. In colorectal tumour xenografts and APCmin/+ transgenic mice, administration of salinomycin significantly reduced tumour growth and the expression of CSC-related Wnt target genes including LGR5. CONCLUSIONS AND IMPLICATIONS: Our study suggested that salinomycin could suppress the growth of colorectal cancer by disrupting the ß-catenin/TCF complex and thus may be a promising agent for colorectal cancer treatment.
