B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival
Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cel...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/13/3530 |
| _version_ | 1797591948900433920 |
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| author | Salwa Alhamad Yassmin Elmasry Isabel Uwagboe Elena Chekmeneva Caroline Sands Benjamin W. Cooper Stephane Camuzeaux Ash Salam Maddy Parsons |
| author_facet | Salwa Alhamad Yassmin Elmasry Isabel Uwagboe Elena Chekmeneva Caroline Sands Benjamin W. Cooper Stephane Camuzeaux Ash Salam Maddy Parsons |
| author_sort | Salwa Alhamad |
| collection | DOAJ |
| description | Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings. |
| first_indexed | 2024-03-11T01:44:51Z |
| format | Article |
| id | doaj.art-2125b51873e4425b998008304b92588f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T01:44:51Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2125b51873e4425b998008304b92588f2023-11-18T16:18:19ZengMDPI AGCancers2072-66942023-07-011513353010.3390/cancers15133530B7-H3 Associates with IMPDH2 and Regulates Cancer Cell SurvivalSalwa Alhamad0Yassmin Elmasry1Isabel Uwagboe2Elena Chekmeneva3Caroline Sands4Benjamin W. Cooper5Stephane Camuzeaux6Ash Salam7Maddy Parsons8Randall Centre for Cell and Molecular Biophysics, King’s College London, Guys Campus, New Hunts House, London SE1 1UL, UKRandall Centre for Cell and Molecular Biophysics, King’s College London, Guys Campus, New Hunts House, London SE1 1UL, UKRandall Centre for Cell and Molecular Biophysics, King’s College London, Guys Campus, New Hunts House, London SE1 1UL, UKNational Phenome Centre, Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, IRDB Building, 5th Floor, Du Cane Road, London W12 0NN, UKNational Phenome Centre, Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, IRDB Building, 5th Floor, Du Cane Road, London W12 0NN, UKNational Phenome Centre, Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, IRDB Building, 5th Floor, Du Cane Road, London W12 0NN, UKNational Phenome Centre, Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, IRDB Building, 5th Floor, Du Cane Road, London W12 0NN, UKNational Phenome Centre, Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, IRDB Building, 5th Floor, Du Cane Road, London W12 0NN, UKRandall Centre for Cell and Molecular Biophysics, King’s College London, Guys Campus, New Hunts House, London SE1 1UL, UKLung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings.https://www.mdpi.com/2072-6694/15/13/3530B7-H3lung cancerIMPDH2proliferationinvasionoxidative stress |
| spellingShingle | Salwa Alhamad Yassmin Elmasry Isabel Uwagboe Elena Chekmeneva Caroline Sands Benjamin W. Cooper Stephane Camuzeaux Ash Salam Maddy Parsons B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival Cancers B7-H3 lung cancer IMPDH2 proliferation invasion oxidative stress |
| title | B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival |
| title_full | B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival |
| title_fullStr | B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival |
| title_full_unstemmed | B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival |
| title_short | B7-H3 Associates with IMPDH2 and Regulates Cancer Cell Survival |
| title_sort | b7 h3 associates with impdh2 and regulates cancer cell survival |
| topic | B7-H3 lung cancer IMPDH2 proliferation invasion oxidative stress |
| url | https://www.mdpi.com/2072-6694/15/13/3530 |
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