Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells
Abstract The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular sene...
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07284-3 |
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| author | Justin Kim Bryce Brunetti Ayanesh Kumar Ankit Mangla Kord Honda Akihiro Yoshida |
| author_facet | Justin Kim Bryce Brunetti Ayanesh Kumar Ankit Mangla Kord Honda Akihiro Yoshida |
| author_sort | Justin Kim |
| collection | DOAJ |
| description | Abstract The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced. |
| format | Article |
| id | doaj-art-defd6869fb40476a88c7b2bbb99aa798 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-defd6869fb40476a88c7b2bbb99aa7982025-08-20T02:31:52ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211310.1038/s41419-024-07284-3Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cellsJustin Kim0Bryce Brunetti1Ayanesh Kumar2Ankit Mangla3Kord Honda4Akihiro Yoshida5Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical CenterDepartment of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical CenterDepartment of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical CenterDepartment of Hematology and Oncology, Case Western Reserve University and University Hospitals Cleveland Medical CenterDepartment of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical CenterDepartment of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical CenterAbstract The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.https://doi.org/10.1038/s41419-024-07284-3 |
| spellingShingle | Justin Kim Bryce Brunetti Ayanesh Kumar Ankit Mangla Kord Honda Akihiro Yoshida Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells Cell Death and Disease |
| title | Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells |
| title_full | Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells |
| title_fullStr | Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells |
| title_full_unstemmed | Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells |
| title_short | Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells |
| title_sort | inhibition of glutaminase elicits senolysis in therapy induced senescent melanoma cells |
| url | https://doi.org/10.1038/s41419-024-07284-3 |
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