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1.
Oncogene ; 39(41): 6421-6436, 2020 10.
Article in English | MEDLINE | ID: mdl-32868877

ABSTRACT

Breast cancer progression is accompanied by increased expression of extracellular and cell-surface proteases capable of degrading the extracellular matrix as well as cleaving and activating downstream targets. The type II transmembrane serine proteases (TTSPs) are a family of cell-surface proteases that play critical roles in numerous types of cancers. Therefore, the aim of this study was to identify novel and uncharacterized TTSPs with differential expression in breast cancer and to determine their potential roles in progression. Systematic in silico data analysis followed by immunohistochemical validation identified increased expression of the TTSP family member, TMPRSS13 (transmembrane protease, serine 13), in invasive ductal carcinoma patient tissue samples compared to normal breast tissue. To test whether loss of TMPRSS13 impacts tumor progression, TMPRSS13 was genetically ablated in the oncogene-induced transgenic MMTV-PymT tumor model. TMPRSS13 deficiency resulted in a significant decrease in overall tumor burden and growth rate, as well as a delayed formation of detectable mammary tumors, thus suggesting a causal relationship between TMPRSS13 expression and the progression of breast cancer. Complementary studies using human breast cancer cell culture models revealed that siRNA-mediated silencing of TMPRSS13 expression decreases proliferation, induces apoptosis, and attenuates invasion. Importantly, targeting TMPRSS13 expression renders aggressive triple-negative breast cancer cell lines highly responsive to chemotherapy. At the molecular level, knockdown of TMPRSS13 in breast cancer cells led to increased protein levels of the tumor-suppressive protease prostasin. TMPRSS13/prostasin co-immunoprecipitation and prostasin zymogen activation experiments identified prostasin as a potential novel target for TMPRSS13. Regulation of prostasin levels may be a mechanism that contributes to the pro-oncogenic properties of TMPRSS13 in breast cancer. TMPRSS13 represents a novel candidate for targeted therapy in combination with standard of care chemotherapy agents in patients with hormone receptor-negative breast cancer or in patients with tumors refractory to endocrine therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Ductal, Breast/pathology , Mammary Neoplasms, Experimental/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Breast/pathology , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/genetics , Cell Line, Tumor , Cell Survival/genetics , Datasets as Topic , Disease Progression , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/genetics , Membrane Proteins/genetics , Mice , Mice, Knockout , Serine Endopeptidases/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics
2.
Sci Rep ; 10(1): 13896, 2020 08 17.
Article in English | MEDLINE | ID: mdl-32807808

ABSTRACT

Cancer progression is often accompanied by increased levels of extracellular proteases capable of remodeling the extracellular matrix and promoting pro-cancerous signaling pathways by activating growth factors and receptors. The type II transmembrane serine protease (TTSP) family encompasses several proteases that play critical roles in cancer progression; however, the expression or function of the TTSP TMPRSS13 in carcinogenesis has not been examined. In the present study, we found TMPRSS13 to be differentially expressed at both the transcript and protein levels in human colorectal cancer (CRC). Immunohistochemical analyses revealed consistent high expression of TMPRSS13 protein on the cancer cell surface in CRC patient samples; in contrast, the majority of normal colon samples displayed no detectable expression. On a functional level, TMPRSS13 silencing in CRC cell lines increased apoptosis and impaired invasive potential. Importantly, transgenic overexpression of TMPRSS13 in CRC cell lines increased tolerance to apoptosis-inducing agents, including paclitaxel and HA14-1. Conversely, TMPRSS13 silencing rendered CRC cells more sensitive to these agents. Together, our findings suggest that TMPRSS13 plays an important role in CRC cell survival and in promoting resistance to drug-induced apoptosis; we also identify TMPRSS13 as a potential new target for monotherapy or combination therapy with established chemotherapeutics to improve treatment outcomes in CRC patients.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing/drug effects , Humans , Membrane Proteins/genetics , Neoplasm Invasiveness , RNA, Messenger/genetics , RNA, Messenger/metabolism , Serine Endopeptidases/genetics , Up-Regulation/drug effects , Up-Regulation/genetics
3.
J Biol Chem ; 292(36): 14867-14884, 2017 09 08.
Article in English | MEDLINE | ID: mdl-28710277

ABSTRACT

TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Although various TTSPs have been characterized in detail biochemically and functionally, the basic properties of TMPRSS13 remain unclear. Here, we investigate the activation, inhibition, post-translational modification, and localization of TMPRSS13. We show that TMPRSS13 is a glycosylated, active protease and that its own proteolytic activity mediates zymogen cleavage. Full-length, active TMPRSS13 exhibits impaired cell-surface expression in the absence of the cognate Kunitz-type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 or HAI-2. Concomitant presence of TMPRSS13 with either HAI-1 or -2 mediates phosphorylation of residues in the intracellular domain of the protease, and it coincides with efficient transport of the protease to the cell surface and its subsequent shedding. Cell-surface labeling experiments indicate that the dominant form of TMPRSS13 on the cell surface is phosphorylated, whereas intracellular TMPRSS13 is predominantly non-phosphorylated. These data provide novel insight into the cellular properties of TMPRSS13 and highlight phosphorylation of TMPRSS13 as a novel post-translational modification of this TTSP family member and potentially other members of this family of proteases.


Subject(s)
Membrane Glycoproteins/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Proteinase Inhibitory Proteins, Secretory/metabolism , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , HEK293 Cells , Humans , Membrane Proteins/genetics , Phosphorylation , Serine Endopeptidases/genetics
4.
Oncotarget ; 7(36): 58162-58173, 2016 Sep 06.
Article in English | MEDLINE | ID: mdl-27528224

ABSTRACT

The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC. We examined the functional relationship between matriptase and the HGF/c-MET signaling pathway in the IBC cell lines SUM149 and SUM190, and in IBC patient samples. Matriptase and c-Met proteins are localized on the surface membrane of IBC cells and their expression is strongly correlated in infiltrating cancer cells and in the cancer cells of lymphatic emboli in patient samples. Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. These data show the potential of matriptase inhibitors as a novel targeted therapy for IBC, and lay the groundwork for the development and testing of such drugs.


Subject(s)
Hepatocyte Growth Factor/metabolism , Inflammatory Breast Neoplasms/pathology , Proto-Oncogene Proteins c-met/metabolism , Serine Endopeptidases/metabolism , Cell Culture Techniques/methods , Cell Line, Tumor , Cell Membrane/metabolism , Cell Proliferation , Female , Humans , Immunohistochemistry , Neoplasm Invasiveness , Protein Precursors/metabolism , Proteolysis/drug effects , RNA Interference , RNA, Small Interfering/metabolism , Serine Endopeptidases/genetics , Signal Transduction
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