CVS‐3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts

Galkin, Anna; Mullen, Linda; Fox, William P.; Brown, Jerry L.; Duncan, David; Moreno, Ofir; Madison, Edwin L.; Agus, David B.

doi:10.1002/pros.20094

Cited by 84 publications

(68 citation statements)

References 26 publications

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“…It is intriguing to consider that TMPRSS4 may modulate the activation of MAPKs to contribute to a malignant phenotype of cancer cells. Our study appears to provide the first evidence that a TTSP family member is positively involved in cancer cell proliferation in vitro; others have reported that inhibition of matriptase/MT-SP1 or TMPRSS1/ hepsin does not affect cell proliferation in vitro, although cell invasion is impaired (Galkin et al, 2004;Suzuki et al, 2004;Forbs et al, 2005;Xuan et al, 2006). However, in contrast to the reduced cell proliferation observed following knockdown of TMPRSS4 in NCI-H322 cells, TMPRSS4 overexpression does not appear to confer a growth advantage to colon cancer SW480 cells in vitro.…”

Section: Discussionmentioning

confidence: 48%

“…Matriptase/MT-SP1, a TTSP with gelatinase activity, is highly expressed in breast, prostate, ovarian and colorectal cancers (Lin et al, 1999;Benaud et al, 2002;NetzelArnett et al, 2003;List et al, 2006). Matriptase/MT-SP1 is also implicated in tumor growth and metastasis in a mouse model of prostate cancer (Takeuchi et al, 1999;Galkin et al, 2004) and induces skin tumorigenesis in a transgenic mouse model (List et al, 2005). Another TTSP, TMPRSS1/hepsin, is highly expressed in hepatomas and ovarian and prostate cancers .…”

Section: Introductionmentioning

confidence: 99%

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TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

et al. 2007

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an Ecadherin transcriptional repressor, and led to epithelialmesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

et al. 2007

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“…Given this and the data supporting MT-SP1, MSP-1, and RON expression in various cancer tissues, we suggest that this pathway may be important in tumor development, maintenance, and/or progression. MT-SP1, MSP-1, and RON have all been established as cancerassociated molecules (2,17,33,34). We suggest that cancer cells may ''hijack'' this signaling pathway by increasing coordinate expression of MT-SP1, MSP-1, and RON to drive proliferation and migration, two fundamental traits of transformed cells.…”

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confidence: 91%

“…Targeted overexpression of MT-SP1 in squamous epithelia in mice results in skin-limited nodules of squamous cell carcinoma that become metastatic in the presence of the chemical carcinogen DMBA (10). Small molecule and macromolecular inhibitors of MT-SP1 have been developed and applied in a mouse model of cancer, resulting in growth suppression of androgen-independent prostate cancer xenografts (2,11). Taken together, these findings suggest a role for MT-SP1 in cancer.…”

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confidence: 93%

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Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Bhatt

Welm

Farady

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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A multidisciplinary method combining transcriptional data, specificity profiling, and biological characterization of an enzyme may be used to predict novel substrates. By integrating protease substrate profiling with microarray gene coexpression data from nearly 2,000 human normal and cancerous tissue samples, three fundamental components of a protease-activated signaling pathway were identified. We find that MT-SP1 mediates extracellular signaling by regulating the local activation of the prometastatic growth factor MSP-1. We demonstrate MT-SP1 expression in peritoneal macrophages, and biochemical methods confirm the ability of MT-SP1 to cleave and activate pro-MSP-1 in vitro and in a cellular context. MT-SP1 induced the ability of MSP-1 to inhibit nitric oxide production in bone marrow macrophages. Addition of HAI-1 or an MT-SP1-specific antibody inhibitor blocked the proteolytic activation of MSP-1 at the cell surface of peritoneal macrophages. Taken together, our work indicates that MT-SP1 is sufficient for MSP-1 activation and that MT-SP1, MSP-1, and the previously shown MSP-1 tyrosine kinase receptor RON are required for peritoneal macrophage activation. This work shows that this triad of growth factor, growth factor activator protease, and growth factor receptor is a protease-activated signaling pathway. Individually, MT-SP1 and RON overexpression have been implicated in cancer progression and metastasis. Transcriptional coexpression of these genes suggests that this signaling pathway may be involved in several human cancers.cancer ͉ macrophage activation ͉ protease substrate specificity ͉ proteomics D espite the successful physiological and biochemical characterization of many proteases, the vast majority of the Ͼ2% of the human genome that encodes proteases has yet to be functionally classified. Although many approaches demonstrate the sufficiency of a protease to cleave a given substrate, very few are able to address the physiological relevance of such in vitro findings. Cell-surface proteolysis is suggested to play a major role in cancer progression and metastasis through the processing of macromolecules important for regulating the extracellular environment. The cell-surface localization, high activity, and exquisite specificity of type II transmembrane serine proteases (TTSPs) suggest a role in outside-in signaling and interaction with the microenvironment. We elected to apply a multifaceted approach to identify physiologically relevant substrates of one prominent member of this family, membrane type serine protease 1 (MT-SP1/matriptase).Members of the TTSP family, such as hepsin and MT-SP1, are highly expressed in many cancers, including those of the prostate, breast, colon, and ovary (1-9). Both overexpression and inhibition studies have supported the role of MT-SP1 in tumorigenesis and tumor growth. Targeted overexpression of MT-SP1 in squamous epithelia in mice results in skin-limited nodules of squamous cell carcinoma that become metastatic in the presence of the chemical carcinogen DMBA (10). ...

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Cancer Diagnostics of Protease Activity and Metastasis

O’Brien¹,

Beard²

2018

Extracellular Targeting of Cell Signaling in Cancer

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CVS‐3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts

Abstract: These results identify CVS-3983 as a potent inhibitor of AI prostate cancer cell invasion in vitro and established xenograft tumor growth in vivo.

Cited by 84 publications

References 26 publications

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Cancer Diagnostics of Protease Activity and Metastasis

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