Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma
Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific in...
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MDPI AG
2020-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/1/30 |
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| author | Jessica Guenzle Harue Akasaka Katharina Joechle Wilfried Reichardt Aina Venkatasamy Jens Hoeppner Claus Hellerbrand Stefan Fichtner-Feigl Sven A. Lang |
| author_facet | Jessica Guenzle Harue Akasaka Katharina Joechle Wilfried Reichardt Aina Venkatasamy Jens Hoeppner Claus Hellerbrand Stefan Fichtner-Feigl Sven A. Lang |
| author_sort | Jessica Guenzle |
| collection | DOAJ |
| description | Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma. |
| first_indexed | 2024-03-10T13:51:34Z |
| format | Article |
| id | doaj.art-7e321b5aadb8416f8c83793d9d50239c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:51:34Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7e321b5aadb8416f8c83793d9d50239c2023-11-21T02:05:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-012213010.3390/ijms22010030Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in MelanomaJessica Guenzle0Harue Akasaka1Katharina Joechle2Wilfried Reichardt3Aina Venkatasamy4Jens Hoeppner5Claus Hellerbrand6Stefan Fichtner-Feigl7Sven A. Lang8Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyDepartment of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyDepartment of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyGerman Cancer Consortium (DKTK), 69120 Heidelberg, GermanyDepartment of Radiology Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Killianstrasse 5a, 79106 Freiburg, GermanyDepartment of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyInstitute of Biochemistry, Friedrich–Alexander University Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, GermanyDepartment of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyDepartment of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, GermanyDespite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.https://www.mdpi.com/1422-0067/22/1/30mTORC2melanomamigrationmetastasis |
| spellingShingle | Jessica Guenzle Harue Akasaka Katharina Joechle Wilfried Reichardt Aina Venkatasamy Jens Hoeppner Claus Hellerbrand Stefan Fichtner-Feigl Sven A. Lang Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma International Journal of Molecular Sciences mTORC2 melanoma migration metastasis |
| title | Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma |
| title_full | Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma |
| title_fullStr | Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma |
| title_full_unstemmed | Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma |
| title_short | Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma |
| title_sort | pharmacological inhibition of mtorc2 reduces migration and metastasis in melanoma |
| topic | mTORC2 melanoma migration metastasis |
| url | https://www.mdpi.com/1422-0067/22/1/30 |
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