Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer
TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-01-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/3/739 |
| _version_ | 1797488746111696896 |
|---|---|
| author | Lei Duan Sarah Calhoun Ricardo E. Perez Virgilia Macias Fatima Mir Melissa R. Pergande Paolo Gattuso Jeffrey A. Borgia Carl G. Maki |
| author_facet | Lei Duan Sarah Calhoun Ricardo E. Perez Virgilia Macias Fatima Mir Melissa R. Pergande Paolo Gattuso Jeffrey A. Borgia Carl G. Maki |
| author_sort | Lei Duan |
| collection | DOAJ |
| description | TNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment. |
| first_indexed | 2024-03-10T00:06:43Z |
| format | Article |
| id | doaj.art-df76e54c7206438ca2873b242791d130 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:06:43Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-df76e54c7206438ca2873b242791d1302023-11-23T16:07:53ZengMDPI AGCancers2072-66942022-01-0114373910.3390/cancers14030739Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast CancerLei Duan0Sarah Calhoun1Ricardo E. Perez2Virgilia Macias3Fatima Mir4Melissa R. Pergande5Paolo Gattuso6Jeffrey A. Borgia7Carl G. Maki8Department of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USADepartment of Pathology, University of Illinois at Chicago, 909 S. Wolcott St, Rm 6128, Chicago, IL 60612, USADepartment of Pathology, Rush University Medical Center, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USADepartment of Pathology, Rush University Medical Center, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USADepartment of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Ave, AcFac 507, Chicago, IL 60612, USATNBC is an aggressive cancer sub-type with limited treatment options and poor prognosis. New therapeutic targets are needed to improve outcomes in TNBC patients. PRCP is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. A role for PRCP in TNBC or other cancers, and its potential as a therapy target has not yet been tested. In the current study, we found high tumor expression of PRCP associates with worse outcome and earlier recurrence in TNBC patients. Knockdown of PRCP or treatment with a small molecule PRCP inhibitor blocked proliferation and survival in TNBC cell lines and inhibited growth of TNBC tumors in mice. Mechanistically, we found PRCP maintains signaling from multiple receptor tyrosine kinases (RTKs), potentially by promoting crosstalk between RTKs and G-protein coupled receptors (GPCRs). Lastly, we found that the PRCP inhibitor caused synergistic killing of TNBC cells when combined with the EGFR and ErbB2 inhibitor lapatinib. Our results suggest that PRCP is potential prognostic marker for TNBC patient outcome and a novel therapeutic target for TNBC treatment.https://www.mdpi.com/2072-6694/14/3/739prolylcarboxypeptidasetriple negative breast cancerprognosisreceptor tyrosine kinasesG-protein coupled receptorstargeted therapy |
| spellingShingle | Lei Duan Sarah Calhoun Ricardo E. Perez Virgilia Macias Fatima Mir Melissa R. Pergande Paolo Gattuso Jeffrey A. Borgia Carl G. Maki Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer Cancers prolylcarboxypeptidase triple negative breast cancer prognosis receptor tyrosine kinases G-protein coupled receptors targeted therapy |
| title | Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer |
| title_full | Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer |
| title_fullStr | Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer |
| title_full_unstemmed | Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer |
| title_short | Prolyl Carboxypeptidase Maintains Receptor Tyrosine Kinase Signaling and Is a Potential Therapeutic Target in Triple Negative Breast Cancer |
| title_sort | prolyl carboxypeptidase maintains receptor tyrosine kinase signaling and is a potential therapeutic target in triple negative breast cancer |
| topic | prolylcarboxypeptidase triple negative breast cancer prognosis receptor tyrosine kinases G-protein coupled receptors targeted therapy |
| url | https://www.mdpi.com/2072-6694/14/3/739 |
| work_keys_str_mv | AT leiduan prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT sarahcalhoun prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT ricardoeperez prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT virgiliamacias prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT fatimamir prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT melissarpergande prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT paologattuso prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT jeffreyaborgia prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer AT carlgmaki prolylcarboxypeptidasemaintainsreceptortyrosinekinasesignalingandisapotentialtherapeutictargetintriplenegativebreastcancer |