Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance
Abstract Squamous cell carcinoma (SCC) poses a significant global health challenge due to the lack of effective treatments. Boron neutron capture therapy (BNCT), a targeted particle therapy, has shown promising results in various cancers. SLC7A5, a transporter of essential amino acids and boronophen...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-025-00568-z |
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| author | Yen-Ju Lin Yu-Cheng Wu Yu-Jui Liu Wei-Chen Yeh Yi-Chen Huang Shen-Ao Zhang Alvin Chen Ming-Yi Zheng Hong-Ming Liu Fong-In Chou Shien-Tung Pan Min-Yuan Chou Yu-Ting Chou |
| author_facet | Yen-Ju Lin Yu-Cheng Wu Yu-Jui Liu Wei-Chen Yeh Yi-Chen Huang Shen-Ao Zhang Alvin Chen Ming-Yi Zheng Hong-Ming Liu Fong-In Chou Shien-Tung Pan Min-Yuan Chou Yu-Ting Chou |
| author_sort | Yen-Ju Lin |
| collection | DOAJ |
| description | Abstract Squamous cell carcinoma (SCC) poses a significant global health challenge due to the lack of effective treatments. Boron neutron capture therapy (BNCT), a targeted particle therapy, has shown promising results in various cancers. SLC7A5, a transporter of essential amino acids and boronophenylalanine (BPA) used in BNCT, emerges as a potential therapeutic target. However, its expression across different histological subtypes and the role of SLC7A5 inhibition in developing drug resistance to BPA-BNCT remain poorly understood. Our study reveals elevated SLC7A5 expression in most SCCs, particularly in lung squamous cell carcinoma (LUSC), where it is significantly higher compared to other lung cancer subtypes. Increased SLC7A5 expression and a higher tumor-to-normal (T/N) ratio in LUSC are associated with poor patient prognosis. SLC7A5 knockdown in LUSC cells reduces colony formation and induces apoptosis. RNA-seq analysis of SLC7A5 knockout LUSC cells shows downregulated mTORC1 signaling, reduced expression of other amino acid transporters, and upregulated autophagy genes, indicating a potential cancer metabolic shift. Furthermore, SLC7A5 knockout LUSC cells demonstrate resistance to BPA-BNCT but sensitivity to the autophagy inhibitor chloroquine. Post-BPA-BNCT treatment, surviving wild-type LUSC cells exhibit reduced SLC7A5 levels and increased sensitivity to chloroquine, highlighting a vulnerability in BPA-BNCT-resistant cells. Our findings elucidate the interplay between SLC7A5, mTOR signaling, and autophagy pathways, providing insights into potential strategies to overcome drug resistance in BPA-BNCT therapy. |
| format | Article |
| id | doaj-art-120f05cde243496aaf7adceb4da8230e |
| institution | DOAJ |
| issn | 2157-9024 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-120f05cde243496aaf7adceb4da8230e2025-08-20T03:06:06ZengNature Publishing GroupOncogenesis2157-90242025-07-0114111310.1038/s41389-025-00568-zTargeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistanceYen-Ju Lin0Yu-Cheng Wu1Yu-Jui Liu2Wei-Chen Yeh3Yi-Chen Huang4Shen-Ao Zhang5Alvin Chen6Ming-Yi Zheng7Hong-Ming Liu8Fong-In Chou9Shien-Tung Pan10Min-Yuan Chou11Yu-Ting Chou12Institute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityInstitute of Biotechnology, National Tsing Hua UniversityNuclear Science and Technology Development Center, National Tsing Hua UniversityNuclear Science and Technology Development Center, National Tsing Hua UniversityDepartment of Pathology, China Medical University Hsinchu HospitalInnovation and Advanced Research Office, Biomedical Technology and Device Research Laboratories, Industrial Technology Research InstituteInstitute of Biotechnology, National Tsing Hua UniversityAbstract Squamous cell carcinoma (SCC) poses a significant global health challenge due to the lack of effective treatments. Boron neutron capture therapy (BNCT), a targeted particle therapy, has shown promising results in various cancers. SLC7A5, a transporter of essential amino acids and boronophenylalanine (BPA) used in BNCT, emerges as a potential therapeutic target. However, its expression across different histological subtypes and the role of SLC7A5 inhibition in developing drug resistance to BPA-BNCT remain poorly understood. Our study reveals elevated SLC7A5 expression in most SCCs, particularly in lung squamous cell carcinoma (LUSC), where it is significantly higher compared to other lung cancer subtypes. Increased SLC7A5 expression and a higher tumor-to-normal (T/N) ratio in LUSC are associated with poor patient prognosis. SLC7A5 knockdown in LUSC cells reduces colony formation and induces apoptosis. RNA-seq analysis of SLC7A5 knockout LUSC cells shows downregulated mTORC1 signaling, reduced expression of other amino acid transporters, and upregulated autophagy genes, indicating a potential cancer metabolic shift. Furthermore, SLC7A5 knockout LUSC cells demonstrate resistance to BPA-BNCT but sensitivity to the autophagy inhibitor chloroquine. Post-BPA-BNCT treatment, surviving wild-type LUSC cells exhibit reduced SLC7A5 levels and increased sensitivity to chloroquine, highlighting a vulnerability in BPA-BNCT-resistant cells. Our findings elucidate the interplay between SLC7A5, mTOR signaling, and autophagy pathways, providing insights into potential strategies to overcome drug resistance in BPA-BNCT therapy.https://doi.org/10.1038/s41389-025-00568-z |
| spellingShingle | Yen-Ju Lin Yu-Cheng Wu Yu-Jui Liu Wei-Chen Yeh Yi-Chen Huang Shen-Ao Zhang Alvin Chen Ming-Yi Zheng Hong-Ming Liu Fong-In Chou Shien-Tung Pan Min-Yuan Chou Yu-Ting Chou Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance Oncogenesis |
| title | Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance |
| title_full | Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance |
| title_fullStr | Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance |
| title_full_unstemmed | Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance |
| title_short | Targeting SLC7A5 in lung squamous cell carcinoma: implications for cancer metabolism shift and boron neutron capture therapy resistance |
| title_sort | targeting slc7a5 in lung squamous cell carcinoma implications for cancer metabolism shift and boron neutron capture therapy resistance |
| url | https://doi.org/10.1038/s41389-025-00568-z |
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