Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib
Patients with metastatic colorectal cancer (mCRC) carrying BRAFV600E mutation have worse response to chemotherapy and poor prognosis. The BRAFV600E inhibitor vemurafenib has shown modest efficacy as monotherapy in BRAF-mutated mCRC due to the development of resistance. The aim of this study was to c...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-7737/12/4/608 |
| _version_ | 1827745863560069120 |
|---|---|
| author | Iris Car Antje Dittmann Marko Klobučar Petra Grbčić Sandra Kraljević Pavelić Mirela Sedić |
| author_facet | Iris Car Antje Dittmann Marko Klobučar Petra Grbčić Sandra Kraljević Pavelić Mirela Sedić |
| author_sort | Iris Car |
| collection | DOAJ |
| description | Patients with metastatic colorectal cancer (mCRC) carrying BRAFV600E mutation have worse response to chemotherapy and poor prognosis. The BRAFV600E inhibitor vemurafenib has shown modest efficacy as monotherapy in BRAF-mutated mCRC due to the development of resistance. The aim of this study was to conduct a comparative proteomics profiling of the secretome from vemurafenib-sensitive vs. -resistant colon cancer cells harboring BRAFV600E mutation in order to identify specific secretory features potentially associated with changes in the resistant cells’ phenotype. Towards this aim, we employed two complementary proteomics approaches including two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry and label-free quantitative LC-MS/MS analysis. Obtained results pointed to aberrant regulation of DNA replication and endoplasmic reticulum stress as the major secretome features associated with chemoresistant phenotype. Accordingly, two proteins implicated in these processes including RPA1 and HSPA5/GRP78 were discussed in more details in the context of biological networks and their importance as potential secretome targets for further functional and clinical evaluation. Expression patterns of RPA1 and HSPA5/GRP78 in tumor tissues from colon cancer patients were also found in additional in silico analyses to be associated with BRAFV600E mutation status, which opens the possibility to extrapolate our findings and their clinical implication to other solid tumors harboring BRAFV600E mutation, such as melanoma. |
| first_indexed | 2024-03-11T05:13:30Z |
| format | Article |
| id | doaj.art-dee4e2274faf4734a415be6028a738e8 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-11T05:13:30Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-dee4e2274faf4734a415be6028a738e82023-11-17T18:24:38ZengMDPI AGBiology2079-77372023-04-0112460810.3390/biology12040608Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to VemurafenibIris Car0Antje Dittmann1Marko Klobučar2Petra Grbčić3Sandra Kraljević Pavelić4Mirela Sedić5Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, CroatiaFunctional Genomics Center Zurich, ETH Zurich, Winterthurerstr. 190, Y59 H38, 8057 Zurich, SwitzerlandCentre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, CroatiaFaculty of Medicine, Juraj Dobrila University of Pula, Zagrebačka ul. 30, 52100 Pula, CroatiaFaculty of Health Studies, University of Rijeka, Viktora Cara Emina 5, 51000 Rijeka, CroatiaCentre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, CroatiaPatients with metastatic colorectal cancer (mCRC) carrying BRAFV600E mutation have worse response to chemotherapy and poor prognosis. The BRAFV600E inhibitor vemurafenib has shown modest efficacy as monotherapy in BRAF-mutated mCRC due to the development of resistance. The aim of this study was to conduct a comparative proteomics profiling of the secretome from vemurafenib-sensitive vs. -resistant colon cancer cells harboring BRAFV600E mutation in order to identify specific secretory features potentially associated with changes in the resistant cells’ phenotype. Towards this aim, we employed two complementary proteomics approaches including two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry and label-free quantitative LC-MS/MS analysis. Obtained results pointed to aberrant regulation of DNA replication and endoplasmic reticulum stress as the major secretome features associated with chemoresistant phenotype. Accordingly, two proteins implicated in these processes including RPA1 and HSPA5/GRP78 were discussed in more details in the context of biological networks and their importance as potential secretome targets for further functional and clinical evaluation. Expression patterns of RPA1 and HSPA5/GRP78 in tumor tissues from colon cancer patients were also found in additional in silico analyses to be associated with BRAFV600E mutation status, which opens the possibility to extrapolate our findings and their clinical implication to other solid tumors harboring BRAFV600E mutation, such as melanoma.https://www.mdpi.com/2079-7737/12/4/608BRAFV600Ecolon cancersecretomeBRAF inhibitionvemurafenibDNA replication |
| spellingShingle | Iris Car Antje Dittmann Marko Klobučar Petra Grbčić Sandra Kraljević Pavelić Mirela Sedić Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib Biology BRAFV600E colon cancer secretome BRAF inhibition vemurafenib DNA replication |
| title | Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib |
| title_full | Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib |
| title_fullStr | Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib |
| title_full_unstemmed | Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib |
| title_short | Secretome Screening of BRAFV600E-Mutated Colon Cancer Cells Resistant to Vemurafenib |
| title_sort | secretome screening of brafv600e mutated colon cancer cells resistant to vemurafenib |
| topic | BRAFV600E colon cancer secretome BRAF inhibition vemurafenib DNA replication |
| url | https://www.mdpi.com/2079-7737/12/4/608 |
| work_keys_str_mv | AT iriscar secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib AT antjedittmann secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib AT markoklobucar secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib AT petragrbcic secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib AT sandrakraljevicpavelic secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib AT mirelasedic secretomescreeningofbrafv600emutatedcoloncancercellsresistanttovemurafenib |