Anoikis induction and metastasis suppression by a new integrin αvβ3 inhibitor in human melanoma cell line M21

Zhang, Yongci; Yang, Ming; Ji, Qing; Fan, Daiming; Peng, Hui; Yang, Chunzheng; Xiong, Dongsheng; Zhou, Yuan

doi:10.1007/s10637-010-9616-y

Cited by 16 publications

(12 citation statements)

References 14 publications

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“…Detached cells form cell clusters in the culture supernatant. These tumor cells, however, are resistant to anoikis and can survive for some time [46]–[48]. After enzyme removal, CD44 de novo synthesis reconstitutes its surface expression, and cell cycle resumes after tumor cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

et al. 2014

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The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.

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Section: Discussionmentioning

confidence: 99%

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

et al. 2014

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“…Several studies have shown an association between Integrin signaling and apoptosis/ anoikis. 21,22 For example, Zhang et al 23 described that treatment of melanoma cells with an inhibitor of Integrin aVb3 promotes anoikis and activates caspase cascades. Hence, it is feasible that Dido1-dependent upregulation of Integrin aV in malignant melanoma results in an enhanced resistance to apoptosis.…”

Section: Dido1 Promotes Melanoma Progression S Braig and A-k Bosserhoffmentioning

confidence: 99%

Death inducer-obliterator 1 (Dido1) is a BMP target gene and promotes BMP-induced melanoma progression

Braig

Bosserhoff

2012

Oncogene

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Bone morphogenetic proteins (BMPs) are known to play an important role in melanoma development and progression. However, the downstream targets of BMPs have not been investigated thus far. Therefore, we treated melanoma cell lines with the Smad-specific BMP inhibitor Dorsomorphin and performed a cDNA microarray. We identified death inducer-obliterator 1 (Dido1) as a BMP-specific Smad-regulated target gene, which was confirmed by qRT --PCR, immunofluorescence staining and electrophoretic mobility shift assay experiments. An analysis of Dido1 expression revealed an upregulation of Dido1 levels in melanoma cell lines and tissues compared with normal melanocytes. Colony-formation assays showed that siDido1-transfected cells formed significantly smaller colonies when grown in soft agar compared with control cells. In addition, fluorescenceactivated cell sorting and western blot experiments revealed that transfection of melanoma cells with Dido1 small interfering RNAs led to an upregulation of apoptosis. Furthermore, cell migratory and invasive potentials were strongly reduced in siDido1-transfected cells compared with control cells. Finally, we demonstrated that Dido1 induces the expression of Integrin aV, thereby promoting the attachment, migration, invasion and apoptosis resistance of melanoma cells.Oncogene ( Keywords: malignant melanoma; bone morphogenic protein; Dido1; integrin aV; migration; invasion INTRODUCTION Malignant melanomas represent B4% of all cutaneous cancers, but account for 480% of skin cancer deaths.1 Moreover, the incidence of melanoma continues to rise, with a 460% increase having occurred over the past 30 years.Several studies have shown that the bone morphogenetic protein (BMP) signaling cascade is deregulated in malignant melanoma. BMPs are members of the transforming growth factor-b family. BMPs bind to a heteromeric receptor complex consisting of the membrane-bound type I and type II serine/threonine kinases (BMPRI and BMPRII). Depending on the receptor complex, different signaling pathways can be activated. After binding to the preformed hetero-oligomeric complex, BMPs initiate the phosphorylation and activation of Smad1/5/8, which then heterodimerize with the Co-Smad Smad4. The complex translocates to the nucleus and activates the transcription of BMP-specific target genes.

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“…In M21 (human melanoma cell line) it induced anoikis, lead to decrease of Bcl-2/Bax ratio and survivin proteins, dephosphorylate Tyr925 in the carboxyl region of FAK. It also inhibited the pulmonary metastases in established melanoma pulmonary metastasis mouse model in dose dependent manner [59]. These in vitro and in vivo results established for IH1062 in human melanoma cells is promising development to treat and prevent tumor metastasis.…”

Section: Integrin Antagonists In Tumor and Angiogenesis Inhibitionmentioning

confidence: 71%

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

Santhosh¹

2014

J Cell Sci Ther

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Integrins are heterodimeric molecules that are composed of 18 α-subunits and 8 β-subunits. They exist in 24 distinctive shapes based on combination of these sub-units and are mainly responsible for the adhesion of extracellular matrix (ECM) and immunoglobulin family molecules. Integrins mediate adhesion of epithelial cells to the basement membrane and also help in the migration, proliferation and survival of tumor cells. Studies also reveal that certain integrins act as markers for tumor cells and they also assist in both tumor progression and apoptosis. Studies reveal that unligated integrins in association with caspase 8 result in inhibition of ECM adhesion might result and integrin mediated death (IMD) on the other hand integrins in association with oncogenes or receptor tyrosine kinases can result in enhanced tumorigenesis. Among several types of integrins, αvβ3 and α 5 β 1 have gained importance in anti-angiogenesis studies.Hence the role of antiangiogenesis antagonists has come into light. These include a variety of monoclonal antibodies and peptides. Each one of them has their own mechanism of action and antiangiogenesis activity. Current review aims at studying the phase 1 and 2 trails of these antagonists for anti-angiogenic function.

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Anoikis induction and metastasis suppression by a new integrin αvβ3 inhibitor in human melanoma cell line M21

Cited by 16 publications

References 14 publications

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

A Natural Bacterial-Derived Product, the Metalloprotease Arazyme, Inhibits Metastatic Murine Melanoma by Inducing MMP-8 Cross-Reactive Antibodies

Death inducer-obliterator 1 (Dido1) is a BMP target gene and promotes BMP-induced melanoma progression

Pharmacological and Clinical Importance of Integrin Antagonists in Treatment of Cancer

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