Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance
More than one half melanoma patients have BRAF gene mutation. BRAF inhibitor vemurafenib is an effective medication for these patients. However, acquired resistance is generally inevitable, the mechanisms of which are not fully understood. Cell senescence and senescence-associated secretory phenotyp...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-07-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023049228 |
| _version_ | 1797771523417702400 |
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| author | Jianyu Peng Zijun Lin Weichun Chen Jie Ruan Fan Deng Lin Yao Minla Rao Xingdong Xiong Shun Xu Xiangning Zhang Xinguang Liu Xuerong Sun |
| author_facet | Jianyu Peng Zijun Lin Weichun Chen Jie Ruan Fan Deng Lin Yao Minla Rao Xingdong Xiong Shun Xu Xiangning Zhang Xinguang Liu Xuerong Sun |
| author_sort | Jianyu Peng |
| collection | DOAJ |
| description | More than one half melanoma patients have BRAF gene mutation. BRAF inhibitor vemurafenib is an effective medication for these patients. However, acquired resistance is generally inevitable, the mechanisms of which are not fully understood. Cell senescence and senescence-associated secretory phenotype (SASP) are involved in extensive biological functions. This study was designed to explore the possible role of senescent cells in vemurafenib resistance. The results showed that vemurafenib treatment induced BRAF-mutant but not wild-type melanoma cells into senescence, as manifested by positive β-galactosidase staining, cell cycle arrest, enlarged cellular morphology, and cyclin D1/p-Rb pathway inhibition. However, the senescent cells induced by vemurafenib (SenV) did not display DNA damage response, p53/p21 pathway activation, reactive oxygen species accumulation, decline of mitochondrial membrane potential, or secretion of canonical SASP cytokines. Instead, SenV released other cytokines, including CCL2, TIMP2, and NGFR, to protect normal melanoma cells from growth inhibition upon vemurafenib treatment. Xenograft experiments further confirmed that vemurafenib induced melanoma cells into senescence in vivo. The results suggest that vemurafenib can induce robust senescence in BRAFV600E melanoma cells, leading to the release of resistance-conferring cytokines. Both the senescent cells and the resistant cytokines could be potential targets for tackling vemurafenib resistance. |
| first_indexed | 2024-03-12T21:38:48Z |
| format | Article |
| id | doaj.art-c7ba70ee87da4c128eb61ebc0a8a8757 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-12T21:38:48Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-c7ba70ee87da4c128eb61ebc0a8a87572023-07-27T05:57:10ZengElsevierHeliyon2405-84402023-07-0197e17714Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistanceJianyu Peng0Zijun Lin1Weichun Chen2Jie Ruan3Fan Deng4Lin Yao5Minla Rao6Xingdong Xiong7Shun Xu8Xiangning Zhang9Xinguang Liu10Xuerong Sun11Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, China; Department of Laboratory Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510378, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaInstitute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaDepartment of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, ChinaDepartment of Pathophysiology, Chinese-American Tumor Institute, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, ChinaGuangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, China; Corresponding author. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Xincheng Avenue 1#, Songshan Lake District, Dongguan 523000, China.Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523000, China; Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, 523000, China; Corresponding author. Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Xincheng Avenue 1#, Songshan Lake District, Dongguan 523000, China.More than one half melanoma patients have BRAF gene mutation. BRAF inhibitor vemurafenib is an effective medication for these patients. However, acquired resistance is generally inevitable, the mechanisms of which are not fully understood. Cell senescence and senescence-associated secretory phenotype (SASP) are involved in extensive biological functions. This study was designed to explore the possible role of senescent cells in vemurafenib resistance. The results showed that vemurafenib treatment induced BRAF-mutant but not wild-type melanoma cells into senescence, as manifested by positive β-galactosidase staining, cell cycle arrest, enlarged cellular morphology, and cyclin D1/p-Rb pathway inhibition. However, the senescent cells induced by vemurafenib (SenV) did not display DNA damage response, p53/p21 pathway activation, reactive oxygen species accumulation, decline of mitochondrial membrane potential, or secretion of canonical SASP cytokines. Instead, SenV released other cytokines, including CCL2, TIMP2, and NGFR, to protect normal melanoma cells from growth inhibition upon vemurafenib treatment. Xenograft experiments further confirmed that vemurafenib induced melanoma cells into senescence in vivo. The results suggest that vemurafenib can induce robust senescence in BRAFV600E melanoma cells, leading to the release of resistance-conferring cytokines. Both the senescent cells and the resistant cytokines could be potential targets for tackling vemurafenib resistance.http://www.sciencedirect.com/science/article/pii/S2405844023049228MelanomaResistanceVemurafenibCell senescenceCytokinesBRAF inhibitors |
| spellingShingle | Jianyu Peng Zijun Lin Weichun Chen Jie Ruan Fan Deng Lin Yao Minla Rao Xingdong Xiong Shun Xu Xiangning Zhang Xinguang Liu Xuerong Sun Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance Heliyon Melanoma Resistance Vemurafenib Cell senescence Cytokines BRAF inhibitors |
| title | Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| title_full | Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| title_fullStr | Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| title_full_unstemmed | Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| title_short | Vemurafenib induces a noncanonical senescence-associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| title_sort | vemurafenib induces a noncanonical senescence associated secretory phenotype in melanoma cells which promotes vemurafenib resistance |
| topic | Melanoma Resistance Vemurafenib Cell senescence Cytokines BRAF inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023049228 |
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