Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer
Various cancer types including head and neck squamous cell carcinomas (HNSCC) show a frequent amplification of chromosomal region 3q26 that encodes, among others, for the SEC62 gene. Located in the ER membrane, this translocation protein is known to play a critical role as a potential driver oncogen...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.880004/full |
| _version_ | 1798040031480250368 |
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| author | Sandrina Körner Tillman Pick Florian Bochen Silke Wemmert Christina Körbel Michael D. Menger Adolfo Cavalié Jan-Philipp Kühn Bernhard Schick Maximilian Linxweiler |
| author_facet | Sandrina Körner Tillman Pick Florian Bochen Silke Wemmert Christina Körbel Michael D. Menger Adolfo Cavalié Jan-Philipp Kühn Bernhard Schick Maximilian Linxweiler |
| author_sort | Sandrina Körner |
| collection | DOAJ |
| description | Various cancer types including head and neck squamous cell carcinomas (HNSCC) show a frequent amplification of chromosomal region 3q26 that encodes, among others, for the SEC62 gene. Located in the ER membrane, this translocation protein is known to play a critical role as a potential driver oncogene in cancer development. High SEC62 expression levels were observed in various cancer entities and were associated with a poor outcome and increased metastatic burden. Because of its intracellular localization the SEC62 protein is poorly accessible for therapeutic antibodies, therefore a functional SEC62 knockdown represents the most promising mechanism of a potential antineoplastic targeted therapy. By stimulating the Ca2+ efflux from the ER lumen and thereby increasing cellular stress levels, a functional inhibition of SEC62 bears the potential to limit tumor growth and metastasis formation. In this study, two potential anti-metastatic and -proliferative agents that counteract SEC62 function were investigated in functional in vitro assays by utilizing an immortalized human hypopharyngeal cancer cell line as well as a newly established orthotopic murine in vivo model. Additionally, a CRISPR/Cas9 based SEC62 knockout HNSCC cell line was generated and functionally characterized for its relevance in HNSCC cell proliferation and migration as well as sensitivity to SEC62 targeted therapy in vitro. |
| first_indexed | 2024-04-11T22:01:54Z |
| format | Article |
| id | doaj.art-0426341b74634c209f3abae9d889c5c9 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T22:01:54Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-0426341b74634c209f3abae9d889c5c92022-12-22T04:00:53ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-08-011310.3389/fphys.2022.880004880004Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancerSandrina Körner0Tillman Pick1Florian Bochen2Silke Wemmert3Christina Körbel4Michael D. Menger5Adolfo Cavalié6Jan-Philipp Kühn7Bernhard Schick8Maximilian Linxweiler9Department of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Pre-Clinical Center for Molecular Signalling (PSMZ), Saarland University, Homburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyInstitute for Clinical and Experimental Surgery, Saarland University, Homburg, GermanyInstitute for Clinical and Experimental Surgery, Saarland University, Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Pre-Clinical Center for Molecular Signalling (PSMZ), Saarland University, Homburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyDepartment of Otorhinolaryngology, Head and Neck Surgery, Saarland University Medical Center, Homburg, GermanyVarious cancer types including head and neck squamous cell carcinomas (HNSCC) show a frequent amplification of chromosomal region 3q26 that encodes, among others, for the SEC62 gene. Located in the ER membrane, this translocation protein is known to play a critical role as a potential driver oncogene in cancer development. High SEC62 expression levels were observed in various cancer entities and were associated with a poor outcome and increased metastatic burden. Because of its intracellular localization the SEC62 protein is poorly accessible for therapeutic antibodies, therefore a functional SEC62 knockdown represents the most promising mechanism of a potential antineoplastic targeted therapy. By stimulating the Ca2+ efflux from the ER lumen and thereby increasing cellular stress levels, a functional inhibition of SEC62 bears the potential to limit tumor growth and metastasis formation. In this study, two potential anti-metastatic and -proliferative agents that counteract SEC62 function were investigated in functional in vitro assays by utilizing an immortalized human hypopharyngeal cancer cell line as well as a newly established orthotopic murine in vivo model. Additionally, a CRISPR/Cas9 based SEC62 knockout HNSCC cell line was generated and functionally characterized for its relevance in HNSCC cell proliferation and migration as well as sensitivity to SEC62 targeted therapy in vitro.https://www.frontiersin.org/articles/10.3389/fphys.2022.880004/fullSec62head and neck cancerCRISPR/ Cas9lymphogenic metastasisxenograft modeltrifluoperazine |
| spellingShingle | Sandrina Körner Tillman Pick Florian Bochen Silke Wemmert Christina Körbel Michael D. Menger Adolfo Cavalié Jan-Philipp Kühn Bernhard Schick Maximilian Linxweiler Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer Frontiers in Physiology Sec62 head and neck cancer CRISPR/ Cas9 lymphogenic metastasis xenograft model trifluoperazine |
| title | Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer |
| title_full | Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer |
| title_fullStr | Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer |
| title_full_unstemmed | Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer |
| title_short | Antagonizing Sec62 function in intracellular Ca2+ homeostasis represents a novel therapeutic strategy for head and neck cancer |
| title_sort | antagonizing sec62 function in intracellular ca2 homeostasis represents a novel therapeutic strategy for head and neck cancer |
| topic | Sec62 head and neck cancer CRISPR/ Cas9 lymphogenic metastasis xenograft model trifluoperazine |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.880004/full |
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