{"title":"通过氨基酸转运蛋白LAT1抑制顺铂耐药食管鳞状细胞癌的新途径","authors":"Takeru Mozumi, Narumi Harada-Shoji, Yohei Ozawa, Yuto Yamazaki, Ryoyu Niikuni, Kentaro Imai, Yusuke Taniyama, Chiaki Sato, Hiroshi Okamoto, Hirotaka Ishida, Atsushi Kunimitsu, Iku Sasaki-Higashimoto, Chisa Kobayashi, Shozo Furumoto, Takaaki Abe, Takashi Suzuki, Takashi Kamei","doi":"10.1002/cam4.71234","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Esophageal squamous cell carcinoma (ESCC) represents an aggressive cancer type associated with poor prognosis, often treated with neoadjuvant chemotherapy (NAC) using cisplatin-based regimens. However, cisplatin resistance limits therapeutic efficacy, necessitating a deeper understanding of resistance mechanisms. L-type amino acid transporter 1 (LAT1) plays a crucial role in amino acid uptake and is linked to cancer cell survival through activation of the mammalian target of rapamycin (mTOR) pathway. The involvement of LAT1 in cisplatin resistance in ESCC remains unclear.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>LAT1 expression in ESCC patient samples post-NAC was evaluated by immunohistochemistry, and its association with clinicopathological factors and survival outcomes was analyzed. ESCC cell lines with varying cisplatin sensitivities were assessed for LAT1 expression using western blotting. Amino acid metabolism was examined via radiotracer uptake of <sup>18</sup>F-FET and <sup>18</sup>F-FDG. RNA sequencing was conducted to identify differentially expressed genes associated with mTOR signaling and autophagy. Finally, the effect of the LAT1 inhibitor JPH203 on cell proliferation was tested.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>High LAT1 expression was significantly associated with larger tumor size, lymph node metastasis, advanced pathological stage, and poor NAC response. Patients with high LAT1 expression exhibited shorter disease-free survival and overall survival. Cisplatin-resistant ESCC cells (KYSE520) showed elevated LAT1 expression, which further increased following cisplatin treatment. Radiotracer assays revealed that <sup>18</sup>F-FET uptake was significantly higher in KYSE520 after cisplatin treatment compared to the sensitive cell line TE5. RNA sequencing identified regulation of mTOR pathway components and autophagy-related genes in cisplatin-resistant cells. Treatment with JPH203 significantly suppressed cell proliferation, particularly in KYSE520 cells, indicating LAT1's role in sustaining tumor cell survival under chemotherapy stress.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>LAT1 contributes to cisplatin resistance in ESCC by sustaining amino acid metabolism and promoting mTOR-dependent autophagy. Targeting LAT1 with JPH203 enhances cisplatin sensitivity, suggesting that LAT1 inhibition could be a promising therapeutic strategy for overcoming chemoresistance in ESCC.</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"14 17","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.71234","citationCount":"0","resultStr":"{\"title\":\"A Novel Approach for Cisplatin-Resistant Esophageal Squamous Cell Carcinoma via Amino Acid Transporter LAT1 Inhibition\",\"authors\":\"Takeru Mozumi, Narumi Harada-Shoji, Yohei Ozawa, Yuto Yamazaki, Ryoyu Niikuni, Kentaro Imai, Yusuke Taniyama, Chiaki Sato, Hiroshi Okamoto, Hirotaka Ishida, Atsushi Kunimitsu, Iku Sasaki-Higashimoto, Chisa Kobayashi, Shozo Furumoto, Takaaki Abe, Takashi Suzuki, Takashi Kamei\",\"doi\":\"10.1002/cam4.71234\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Esophageal squamous cell carcinoma (ESCC) represents an aggressive cancer type associated with poor prognosis, often treated with neoadjuvant chemotherapy (NAC) using cisplatin-based regimens. However, cisplatin resistance limits therapeutic efficacy, necessitating a deeper understanding of resistance mechanisms. L-type amino acid transporter 1 (LAT1) plays a crucial role in amino acid uptake and is linked to cancer cell survival through activation of the mammalian target of rapamycin (mTOR) pathway. The involvement of LAT1 in cisplatin resistance in ESCC remains unclear.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>LAT1 expression in ESCC patient samples post-NAC was evaluated by immunohistochemistry, and its association with clinicopathological factors and survival outcomes was analyzed. ESCC cell lines with varying cisplatin sensitivities were assessed for LAT1 expression using western blotting. Amino acid metabolism was examined via radiotracer uptake of <sup>18</sup>F-FET and <sup>18</sup>F-FDG. RNA sequencing was conducted to identify differentially expressed genes associated with mTOR signaling and autophagy. Finally, the effect of the LAT1 inhibitor JPH203 on cell proliferation was tested.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>High LAT1 expression was significantly associated with larger tumor size, lymph node metastasis, advanced pathological stage, and poor NAC response. Patients with high LAT1 expression exhibited shorter disease-free survival and overall survival. Cisplatin-resistant ESCC cells (KYSE520) showed elevated LAT1 expression, which further increased following cisplatin treatment. Radiotracer assays revealed that <sup>18</sup>F-FET uptake was significantly higher in KYSE520 after cisplatin treatment compared to the sensitive cell line TE5. RNA sequencing identified regulation of mTOR pathway components and autophagy-related genes in cisplatin-resistant cells. Treatment with JPH203 significantly suppressed cell proliferation, particularly in KYSE520 cells, indicating LAT1's role in sustaining tumor cell survival under chemotherapy stress.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>LAT1 contributes to cisplatin resistance in ESCC by sustaining amino acid metabolism and promoting mTOR-dependent autophagy. Targeting LAT1 with JPH203 enhances cisplatin sensitivity, suggesting that LAT1 inhibition could be a promising therapeutic strategy for overcoming chemoresistance in ESCC.</p>\\n </section>\\n </div>\",\"PeriodicalId\":139,\"journal\":{\"name\":\"Cancer Medicine\",\"volume\":\"14 17\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.71234\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cam4.71234\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cam4.71234","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
A Novel Approach for Cisplatin-Resistant Esophageal Squamous Cell Carcinoma via Amino Acid Transporter LAT1 Inhibition
Background
Esophageal squamous cell carcinoma (ESCC) represents an aggressive cancer type associated with poor prognosis, often treated with neoadjuvant chemotherapy (NAC) using cisplatin-based regimens. However, cisplatin resistance limits therapeutic efficacy, necessitating a deeper understanding of resistance mechanisms. L-type amino acid transporter 1 (LAT1) plays a crucial role in amino acid uptake and is linked to cancer cell survival through activation of the mammalian target of rapamycin (mTOR) pathway. The involvement of LAT1 in cisplatin resistance in ESCC remains unclear.
Methods
LAT1 expression in ESCC patient samples post-NAC was evaluated by immunohistochemistry, and its association with clinicopathological factors and survival outcomes was analyzed. ESCC cell lines with varying cisplatin sensitivities were assessed for LAT1 expression using western blotting. Amino acid metabolism was examined via radiotracer uptake of 18F-FET and 18F-FDG. RNA sequencing was conducted to identify differentially expressed genes associated with mTOR signaling and autophagy. Finally, the effect of the LAT1 inhibitor JPH203 on cell proliferation was tested.
Results
High LAT1 expression was significantly associated with larger tumor size, lymph node metastasis, advanced pathological stage, and poor NAC response. Patients with high LAT1 expression exhibited shorter disease-free survival and overall survival. Cisplatin-resistant ESCC cells (KYSE520) showed elevated LAT1 expression, which further increased following cisplatin treatment. Radiotracer assays revealed that 18F-FET uptake was significantly higher in KYSE520 after cisplatin treatment compared to the sensitive cell line TE5. RNA sequencing identified regulation of mTOR pathway components and autophagy-related genes in cisplatin-resistant cells. Treatment with JPH203 significantly suppressed cell proliferation, particularly in KYSE520 cells, indicating LAT1's role in sustaining tumor cell survival under chemotherapy stress.
Conclusion
LAT1 contributes to cisplatin resistance in ESCC by sustaining amino acid metabolism and promoting mTOR-dependent autophagy. Targeting LAT1 with JPH203 enhances cisplatin sensitivity, suggesting that LAT1 inhibition could be a promising therapeutic strategy for overcoming chemoresistance in ESCC.
期刊介绍：
Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas:
Clinical Cancer Research
Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations
Cancer Biology:
Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery.
Cancer Prevention:
Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach.
Bioinformatics:
Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers.
Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
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