Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis
PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the baseme...
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Published in | Neoplasia (New York, N.Y.) Vol. 12; no. 7; p. 516 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.07.2010
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Subjects | |
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Abstract | PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine kinase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors. |
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AbstractList | PACE4 is a proprotein convertase (PC) responsible for cleaving and activating proteins that contribute to enhance tumor progression. PACE4 overexpression significantly increased the susceptibility to carcinogenesis, leading to enhanced tumor cell proliferation and premature degradation of the basement membrane. In the present study, we sought to evaluate a novel approach to retard skin tumor progression based on the inhibition of PACE4. We used decanoyl-RVKR-chloromethylketone (CMK), a small-molecule PC inhibitor, for in vitro and in vivo experiments. We found that CMK-dependent blockage of PACE4 activity in skin squamous cell carcinoma cell lines resulted in impaired insulin-like growth factor 1 receptor maturation, diminished its intrinsic tyrosine kinase activity, and decreased tumor cell proliferation. Two-stage skin chemical carcinogenesis experiments, together with topical applications of CMK, demonstrated that this PC inhibitor markedly reduced tumor incidence, tumor multiplicity, and metastasis, pointing to a significant delay in tumor progression in wild-type and PACE4 transgenic mice. These results identify PACE4, together with other PCs, as suitable targets to slow down or block tumor progression, suggesting that PC inhibition is a potential approach for therapy for solid tumors. |
Author | Litwin, Samuel Zhang, Jirong Bassi, Daniel E Klein-Szanto, Andres J P Cenna, Jonathan Cukierman, Edna |
Author_xml | – sequence: 1 givenname: Daniel E surname: Bassi fullname: Bassi, Daniel E organization: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA – sequence: 2 givenname: Jirong surname: Zhang fullname: Zhang, Jirong – sequence: 3 givenname: Jonathan surname: Cenna fullname: Cenna, Jonathan – sequence: 4 givenname: Samuel surname: Litwin fullname: Litwin, Samuel – sequence: 5 givenname: Edna surname: Cukierman fullname: Cukierman, Edna – sequence: 6 givenname: Andres J P surname: Klein-Szanto fullname: Klein-Szanto, Andres J P |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/20651981$$D View this record in MEDLINE/PubMed |
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SubjectTerms | Amino Acid Chloromethyl Ketones - pharmacology Animals Antineoplastic Agents - pharmacology Carcinoma, Squamous Cell - pathology Cell Line Cell Proliferation - drug effects Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - pathology Down-Regulation - drug effects Enzyme Inhibitors - pharmacology Female Humans Mice Mice, Transgenic Neoplasm Metastasis Proprotein Convertases - antagonists & inhibitors Proprotein Convertases - genetics Skin - drug effects Skin - pathology Skin Neoplasms - pathology Xenograft Model Antitumor Assays |
Title | Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis |
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