GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis
Abstract Background Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods Bioinformatics analysis was conducte...
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BMC
2024-12-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01953-z |
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| author | Wen-Ke Wang Hui-Yu Lin Che-Hsuan Lin Hsun-Hua Lee Yen-Lin Chen Yu-Hsien Kent Lin Hui-Wen Chiu Shry-Ming Sheen-Chen Yuan-Feng Lin |
| author_facet | Wen-Ke Wang Hui-Yu Lin Che-Hsuan Lin Hsun-Hua Lee Yen-Lin Chen Yu-Hsien Kent Lin Hui-Wen Chiu Shry-Ming Sheen-Chen Yuan-Feng Lin |
| author_sort | Wen-Ke Wang |
| collection | DOAJ |
| description | Abstract Background Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein–coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments. Results Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells. Conclusion Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity. |
| format | Article |
| id | doaj-art-de6667a4781b47c0b32dd2b0a045fa4e |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-de6667a4781b47c0b32dd2b0a045fa4e2025-01-05T12:50:41ZengBMCBreast Cancer Research1465-542X2024-12-0126111610.1186/s13058-024-01953-zGRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axisWen-Ke Wang0Hui-Yu Lin1Che-Hsuan Lin2Hsun-Hua Lee3Yen-Lin Chen4Yu-Hsien Kent Lin5Hui-Wen Chiu6Shry-Ming Sheen-Chen7Yuan-Feng Lin8Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityDepartment of Otolaryngology, Taipei Medical University Hospital, Taipei Medical UniversityDepartment of Neurology, Shuang Ho Hospital, Taipei Medical UniversityDepartment of Pathology, Tri-Service General Hospital, National Defense Medical CenterDepartment of Obstetrics and Gynaecology, North Shore Private HospitalGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityDepartment of Surgery, Taipei Medical University Hospital, Taipei Medical UniversityGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical UniversityAbstract Background Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown. Methods Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein–coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments. Results Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells. Conclusion Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.https://doi.org/10.1186/s13058-024-01953-zTriple-negative breast cancerMetastasisGRK6β-Arrestin 2MAPKsNF-κB |
| spellingShingle | Wen-Ke Wang Hui-Yu Lin Che-Hsuan Lin Hsun-Hua Lee Yen-Lin Chen Yu-Hsien Kent Lin Hui-Wen Chiu Shry-Ming Sheen-Chen Yuan-Feng Lin GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis Breast Cancer Research Triple-negative breast cancer Metastasis GRK6 β-Arrestin 2 MAPKs NF-κB |
| title | GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis |
| title_full | GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis |
| title_fullStr | GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis |
| title_full_unstemmed | GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis |
| title_short | GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis |
| title_sort | grk6 palmitoylation dictates triple negative breast cancer metastasis via recruiting the β arrestin 2 mapks nf κb signaling axis |
| topic | Triple-negative breast cancer Metastasis GRK6 β-Arrestin 2 MAPKs NF-κB |
| url | https://doi.org/10.1186/s13058-024-01953-z |
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