Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools
| العنوان: | Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools |
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| المؤلفون: | Michal Stark, Elisa Giovannetti, Gerrit Jansen, Larry H. Matherly, Maria Gemelli, Godefridus J. Peters, Erik Thunnissen, Ittai B. Muller, Zhanjun Hou, P. A. Zucali, E. A. Struys, Niccola Funel, M. Perrino, Yehuda G. Assaraf |
| المساهمون: | Medical oncology laboratory, CCA - Cancer biology and immunology, Pathology, Clinical chemistry, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Rheumatology, AGEM - Digestive immunity |
| المصدر: | Annals of Oncology, 28(11), 2725-2732. Oxford University Press Giovannetti, E, Zucali, P A, Assaraf, Y G, Funel, N, Gemelli, M, Stark, M, Thunnissen, E, Hou, Z, Muller, I B, Struys, E A, Perrino, M, Jansen, G, Matherly, L H & Peters, G J 2017, ' Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma : Clinical evidence and new pharmacological tools ', Annals of Oncology, vol. 28, no. 11, pp. 2725-2732 . https://doi.org/10.1093/annonc/mdx499Test |
| بيانات النشر: | Elsevier BV, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, Mesothelioma, 0301 basic medicine, Oncology, Thymidylate synthase, Immunoenzyme Techniques, Reduced Folate Carrier Protein, chemistry.chemical_compound, 0302 clinical medicine, Tumor Cells, Cultured, Aged, 80 and over, biology, Hematology, Methylation, Middle Aged, Prognosis, Survival Rate, Pemetrexed, 030220 oncology & carcinogenesis, Antifolate, Immunohistochemistry, Female, Proton-Coupled Folate Transporter, medicine.drug, Adult, medicine.medical_specialty, Pleural Neoplasms, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Gene silencing, Survival rate, Aged, Cell Proliferation, business.industry, Original Articles, Thymidylate Synthase, medicine.disease, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, biology.protein, Folic Acid Antagonists, business, Follow-Up Studies |
| الوصف: | Background Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma. Patients and methods PCFT,RFC andTS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed byt-test, Fisher’s/log-rank test and Cox proportional models. The contribution of PCFT expression andPCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2′-deoxycytidine-mediated demethylation and siRNA-knockdown. Results Pemetrexed-treated patients with lowPCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months,P = 0.01) and validation (N = 51, 12.6 versus 30.3 months,P = 0.02) cohorts. Multivariate analysis confirmedPCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found forRFC nor in pemetrexed-untreated patients.PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2′-deoxycytidine overcame resistance. Conclusions These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targetingPCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression. |
| تدمد: | 0923-7534 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ccf6187f967e64fb83a9f2dcd466830Test https://doi.org/10.1093/annonc/mdx499Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6ccf6187f967e64fb83a9f2dcd466830 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 09237534 |
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