ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics
Background Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/7/e004825.full |
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| author | Jin-Ho Choi Joo Dong Park Kwang-Soo Kim Seung Hee Choi Gae Hoon Jo Si-Won Park Eun-Su Ko Minwook Lee Dae-Keum Lee Hye Jung Jang Sohyun Hwang Hae-Yun Jung Kyung-Soon Park |
| author_facet | Jin-Ho Choi Joo Dong Park Kwang-Soo Kim Seung Hee Choi Gae Hoon Jo Si-Won Park Eun-Su Ko Minwook Lee Dae-Keum Lee Hye Jung Jang Sohyun Hwang Hae-Yun Jung Kyung-Soon Park |
| author_sort | Jin-Ho Choi |
| collection | DOAJ |
| description | Background Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment, the therapeutic efficacy of NK cells against TNBC is below expectations. E26 transformation-specific transcription factor ELK3 (ELK3) is highly expressed in TNBCs and functions as a master regulator of the epithelial-mesenchymal transition.Methods Two representative human TNBC cell lines, MDA-MB231 and Hs578T, were exposed to ELK3-targeting shRNA or an ELK3-expressing plasmid to modulate ELK3 expression. The downstream target genes of ELK3 were identified using a combined approach comprising gene expression profiling and molecular analysis. The role of ELK3 in determining the immunosensitivity of TNBC to NK cells was investigated in terms of mitochondrial fission–fusion transition and reactive oxygen species concentration both in vitro and in vivo.Results ELK3-dependent mitochondrial fission–fusion status was linked to the mitochondrial superoxide concentration in TNBCs and was a main determinant of NK cell-mediated immune responses. We identified mitochondrial dynamics proteins of 51 (Mid51), a major mediator of mitochondrial fission, as a direct downstream target of ELK3 in TNBCs. Also, we demonstrated that expression of ELK3 correlated inversely with that of Mid51, and that the ELK3-Mid51 axis is associated directly with the status of mitochondrial dynamics. METABRIC analysis revealed that the ELK3-Mid51 axis has a direct effect on the immune score and survival of patients with TNBC.Conclusions Taken together, the data suggest that NK cell responses to TNBC are linked directly to ELK3 expression levels, shedding new light on strategies to improve the efficacy of NK cell-based immunotherapy of TNBC. |
| first_indexed | 2024-12-10T09:39:29Z |
| format | Article |
| id | doaj.art-2f63601538e64f49aa85bf46af486164 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-10T09:39:29Z |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-2f63601538e64f49aa85bf46af4861642022-12-22T01:54:04ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-07-0110710.1136/jitc-2022-004825ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamicsJin-Ho Choi0Joo Dong Park1Kwang-Soo Kim2Seung Hee Choi3Gae Hoon Jo4Si-Won Park5Eun-Su Ko6Minwook Lee7Dae-Keum Lee8Hye Jung Jang9Sohyun Hwang10Hae-Yun Jung11Kyung-Soon Park12Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaDepartment of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Neurosurgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Department of Biomedical Science, CHA University, Seongnam-si, Korea (the Republic of)Background Triple negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive behavior and frequent development of resistance to chemotherapy. Although natural killer (NK) cell-based immunotherapy is a promising strategy for overcoming barriers to cancer treatment, the therapeutic efficacy of NK cells against TNBC is below expectations. E26 transformation-specific transcription factor ELK3 (ELK3) is highly expressed in TNBCs and functions as a master regulator of the epithelial-mesenchymal transition.Methods Two representative human TNBC cell lines, MDA-MB231 and Hs578T, were exposed to ELK3-targeting shRNA or an ELK3-expressing plasmid to modulate ELK3 expression. The downstream target genes of ELK3 were identified using a combined approach comprising gene expression profiling and molecular analysis. The role of ELK3 in determining the immunosensitivity of TNBC to NK cells was investigated in terms of mitochondrial fission–fusion transition and reactive oxygen species concentration both in vitro and in vivo.Results ELK3-dependent mitochondrial fission–fusion status was linked to the mitochondrial superoxide concentration in TNBCs and was a main determinant of NK cell-mediated immune responses. We identified mitochondrial dynamics proteins of 51 (Mid51), a major mediator of mitochondrial fission, as a direct downstream target of ELK3 in TNBCs. Also, we demonstrated that expression of ELK3 correlated inversely with that of Mid51, and that the ELK3-Mid51 axis is associated directly with the status of mitochondrial dynamics. METABRIC analysis revealed that the ELK3-Mid51 axis has a direct effect on the immune score and survival of patients with TNBC.Conclusions Taken together, the data suggest that NK cell responses to TNBC are linked directly to ELK3 expression levels, shedding new light on strategies to improve the efficacy of NK cell-based immunotherapy of TNBC.https://jitc.bmj.com/content/10/7/e004825.full |
| spellingShingle | Jin-Ho Choi Joo Dong Park Kwang-Soo Kim Seung Hee Choi Gae Hoon Jo Si-Won Park Eun-Su Ko Minwook Lee Dae-Keum Lee Hye Jung Jang Sohyun Hwang Hae-Yun Jung Kyung-Soon Park ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics Journal for ImmunoTherapy of Cancer |
| title | ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| title_full | ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| title_fullStr | ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| title_full_unstemmed | ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| title_short | ELK3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| title_sort | elk3 modulates the antitumor efficacy of natural killer cells against triple negative breast cancer by regulating mitochondrial dynamics |
| url | https://jitc.bmj.com/content/10/7/e004825.full |
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