Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis
Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for p...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000338 |
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| author | Oliver Eckel Madalina A. Mirea Anna Gschwendtner Martina Pistek Katharina Kinslechner Clemens Röhrl Herbert Stangl Markus Hengstschläger Mario Mikula |
| author_facet | Oliver Eckel Madalina A. Mirea Anna Gschwendtner Martina Pistek Katharina Kinslechner Clemens Röhrl Herbert Stangl Markus Hengstschläger Mario Mikula |
| author_sort | Oliver Eckel |
| collection | DOAJ |
| description | Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for potential therapy. We found that SR-B1 depletion in melanoma cells does not alter total cholesterol levels, but induces cholesterol biosynthesis. This effect was characterized by an increased expression of HMG-CoA reductase (HMGCR), a rate limiting enzyme of cholesterol biosynthesis. Notably, further analyses indicated that this regulation occurs at the post-translational level, mediated via the hypoxia-inducible factor (HIF) signaling pathway. Importantly, we identified SR-B1 as a transporter of the lipid hormone sphingosine-1-phosphate (S1P) and we found that S1P exposure leads to HIF1A up-regulation. Finally, we used a pluripotent stem cell-derived skin organoid model to show that targeting SR-B1 in combination with targeted melanoma therapy can lead to increased apoptosis and suppressed proliferation of transplanted tumor cells. Our study shows that functional SR-B1 is linked to inflammatory signaling, which reduces cholesterol synthesis, while enabling melanoma cell survival during chemotherapy treatment. |
| format | Article |
| id | doaj-art-ebff537f431741b09f7077d3729c15ee |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-ebff537f431741b09f7077d3729c15ee2025-08-20T01:55:34ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-05-016310115410.1016/j.neo.2025.101154Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesisOliver Eckel0Madalina A. Mirea1Anna Gschwendtner2Martina Pistek3Katharina Kinslechner4Clemens Röhrl5Herbert Stangl6Markus Hengstschläger7Mario Mikula8Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaUniversity of Applied Sciences Upper Austria, Faculty of Engineering, Stelzhamerstraße 23, 4600, Wels, AustriaInstitute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, AustriaInstitute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria; Corresponding author.Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for potential therapy. We found that SR-B1 depletion in melanoma cells does not alter total cholesterol levels, but induces cholesterol biosynthesis. This effect was characterized by an increased expression of HMG-CoA reductase (HMGCR), a rate limiting enzyme of cholesterol biosynthesis. Notably, further analyses indicated that this regulation occurs at the post-translational level, mediated via the hypoxia-inducible factor (HIF) signaling pathway. Importantly, we identified SR-B1 as a transporter of the lipid hormone sphingosine-1-phosphate (S1P) and we found that S1P exposure leads to HIF1A up-regulation. Finally, we used a pluripotent stem cell-derived skin organoid model to show that targeting SR-B1 in combination with targeted melanoma therapy can lead to increased apoptosis and suppressed proliferation of transplanted tumor cells. Our study shows that functional SR-B1 is linked to inflammatory signaling, which reduces cholesterol synthesis, while enabling melanoma cell survival during chemotherapy treatment.http://www.sciencedirect.com/science/article/pii/S1476558625000338HDL receptorCholesterolS1PHIF1AInflammationBLT-1 |
| spellingShingle | Oliver Eckel Madalina A. Mirea Anna Gschwendtner Martina Pistek Katharina Kinslechner Clemens Röhrl Herbert Stangl Markus Hengstschläger Mario Mikula Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis Neoplasia: An International Journal for Oncology Research HDL receptor Cholesterol S1P HIF1A Inflammation BLT-1 |
| title | Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| title_full | Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| title_fullStr | Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| title_full_unstemmed | Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| title_short | Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| title_sort | expression of the cholesterol transporter sr b1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis |
| topic | HDL receptor Cholesterol S1P HIF1A Inflammation BLT-1 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000338 |
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