Victoria Perrier-Trudova1, Bernice Wong Huimin2, Sarinya Kongpetch3, Dachuan Huang3, Pauline Ong2, Audrey Le Formal4, Song Ling Poon2, Ee Yan Siew3, Swe Swe Myint3, Sophie Gad4, Betty Gardie5, Sophie Couvé4, Yu Miin Foong6, Yukti Choudhury6, Jonathan Poh6, Choon Kiat Ong2, Chee Keong Toh7, Aikseng Ooi8, Stéphane Richard9, Min-Han Tan10, Bin Tean Teh11. 1. Ecole Pratique des Hautes Etudes, Paris and French National Institute of Health and Medical Research U753, Gustave Roussy Cancer Campus, Villejuif, France Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore. 2. Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore Division of Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Republic of Singapore. 3. Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore. 4. Ecole Pratique des Hautes Etudes, Paris and French National Institute of Health and Medical Research U753, Gustave Roussy Cancer Campus, Villejuif, France. 5. French National Institute of Health and Medical Research U892 and French National Centre for Scientific Research 6299, Cancer Research Center Nantes-Angers, University of Nantes, Nantes, France. 6. Department of Biodevices and Diagnostics, Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore. 7. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore. 8. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Arizona, AZ, U.S.A. 9. Ecole Pratique des Hautes Etudes, Paris and French National Institute of Health and Medical Research U753, Gustave Roussy Cancer Campus, Villejuif, France Faculty of Medicine, Paris-Sud University, Kremlin Bicêtre, Paris, France. 10. Department of Biodevices and Diagnostics, Institute of Bioengineering and Nanotechnology, Singapore, Republic of Singapore Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore minhan.tan@gmail.com teh.bin.tean@singhealth.com.sg. 11. Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Republic of Singapore Division of Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Republic of Singapore minhan.tan@gmail.com teh.bin.tean@singhealth.com.sg.
Abstract
BACKGROUND/AIM: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2). MATERIALS AND METHODS: Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti-neoplastic drugs. RESULTS: We established a new in vitro model of hereditary PRCC2 - the NCCFH1 cell line. The cell line possesses a c.1162 delA - p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH(-/-) cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib. CONCLUSION: We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option. Copyright
BACKGROUND/AIM: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2). MATERIALS AND METHODS: Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti-neoplastic drugs. RESULTS: We established a new in vitro model of hereditary PRCC2 - the NCCFH1 cell line. The cell line possesses a c.1162 delA - p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH(-/-) cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib. CONCLUSION: We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option. Copyright
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