Interaction between HSP60 and β-catenin promotes metastasis

Tsai, Ya Ping; Yang, Muh Hwa; Huang, Chih Chia; Chang, Shun‐Hsyung; Chen, Po Min; Liu, Chung Ji; Teng, Shu-Chun; Wu, Kou Juey

doi:10.1093/carcin/bgp087

Cited by 109 publications

(84 citation statements)

References 43 publications

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“…Indeed, loss of P-cadherin expression after PF-03732010 treatment resulted in decreased metastasis without any affect on the E-cadherin level, presumably, in part, due to the reduced tumor cell adhesiveness. More importantly, the antimetastatic activity was derived from the diminished level of β-catenin, which not only plays a functional role in stabilizing P-cadherin-mediated cell-cell adhesion but also regulates molecular signaling pathways to promote tumor growth, invasiveness, and metastasis (17,19). It has been shown that P-cadherin failed to induce invasion when the catenin-binding domain was mutated (38).…”

Section: Discussionmentioning

confidence: 99%

“…P-cadherin-associated tumor cell growth, motility, and invasiveness is likely or at least partially mediated by the relocalization of membrane β-catenin to the cytoplasm and subsequently into the nucleus where it partners with the T-cell factor and activates transcription of the target genes (14,17), including vimentin (18), cyclin D1, survivin, and BCL-2 (19). The upregulation of P-cadherin was frequently observed in various malignant tumors, including breast, colon, lung, and pancreatic tumors, and correlated with poor survival of breast cancer patients (15,20,21).…”

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confidence: 99%

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PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

Zhang

Yan²,

Zhang³

et al. 2010

Clinical Cancer Research

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Purpose: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.Experimental Design: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.Results: PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3′-[18 F]fluoro-3′-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3′-[ 18 F]fluoro-3′-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts. Conclusions: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials. Clin Cancer Res; 16(21); 5177-88. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

Zhang

Yan²,

Zhang³

et al. 2010

Clinical Cancer Research

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“…Nuclear β-catenin is correlated with a poor prognosis in patients with metastasic HNSCC (Tsai et al, 2009). Rap1, a raslike protein, stabilized β-catenin and increased its nuclear localization; more advanced N-stage lesions were associated with high free β-catenin and high active Rap1 (Goto et al, 2010).…”

Section: β-Cateninmentioning

confidence: 99%

Biomarkers of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma

et al. 2012

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An understanding of the process by which tumor cells destroy the basement membrane of the surface epithelium, invade, and metastasize is essential to the development of novel treatment of head and neck squamous cell carcinoma (HNSCC). In recent years, there has been increased interest in the role of epithelial-mesenchymal transition (EMT) in invasion. EMT is a process that describes the development of motile, mesenchymal-like cells from non-motile parent epithelial cells. There are 3 known types of EMT that mediate development, wound healing, and carcinogenesis. This review summarizes studies of known EMT biomarkers in the context of HNSCC progression. The biomarkers discussed come from a wide range of proteins, including cell-surface proteins (E-cadherin, N-cadherin, and Integrins), cytoskeletal proteins (α-Smooth Muscle Actin, Vimentin, and β-catenin), extracellular matrix proteins (Collagens, Fibronectin, and Laminin), and transcription factors (SNAIL1, SNAIL2, TWIST, and LEF-1). Overall, the findings of these studies suggest that EMT mediates HNSCC progression. The mechanistic role of the EMT markers that have been associated with HNSCC should be more clearly defined if new anti-HNSCC therapies to block EMT progression are to be developed.KEY WORDS: disease progression, extracellular matrix, oral pathology, neoplasm invasiveness, biological markers, head and neck neoplasms.

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“…β-catenin is then translocated into the nucleus, where it binds to Tcf/Lef and initiates transcription of its target genes, which include c-myc; this results in cellular canceration (20,28). The β-catenin oncogenic protein is widely expressed in a number of human malignancies (29), including ESCC (30), head and neck squamous cell carcinoma (31)(32)(33) and colorectal cancer (34). Additionally, it has been reported that elevated β-catenin levels promote early neoplastic change through oncogenic signaling within cells (35,36).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of lupeal acetate of Cortex periplocae on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis

Wang

Meng

et al. 2012

Oncology Letters

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Abstract. Lupeal acetate of Cortex periplocae (CPLA), a triterpene compound extracted from a traditional Chinese herb, has been identified as an inhibitor of cancer cell growth. The objective of the present study was to evaluate the potential mechanisms through which CPLA inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. We treated F344 rats subcutaneously with the esophageal carcinogen NMBA (0.5 mg/kg body weight) and intramuscularly with CPLA (20 mg/kg), 3 times a week for 5 weeks. Rats were then sacrificed at weeks 9, 15 or 25, esophageal tissues were collected and tumor data were recorded. To investigate the mechanisms by which CPLA modulates tumorigenesis in esophagus, we evaluated the protein expression of glycogen synthase kinase-3β (GSK-3β) and β-catenin and the gene expression of c-myc. CPLA significantly (P<0.05) reduced the incidence of esophageal tumors observed at 25 weeks from 93.3% in NMBA-treated controls to 33.3% in the NMBAand CPLA-treated rats. CPLA reduced β-catenin and c-myc expression, but increased GSK-3β expression, in preneoplastic lesions of the esophagus. These results suggest a novel tumorsuppressive role of CPLA through the activation of GSK-3β expression and the inhibition of β-catenin and c-myc expression. Therefore, CPLA is a potential therapeutic candidate for esophageal squamous cell carcinoma.

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Interaction between HSP60 and β-catenin promotes metastasis

Cited by 109 publications

References 43 publications

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

Biomarkers of Epithelial-Mesenchymal Transition in Squamous Cell Carcinoma

Inhibitory effects of lupeal acetate of Cortex periplocae on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis

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