Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine‐ and cisplatin‐resistant models
| Title: | Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine‐ and cisplatin‐resistant models |
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| Authors: | Ichiro Kawahara, Hirofumi Yoshino, Wataru Fukumoto, Junya Arima, Saeki Saito, Gang Li, Ikumi Fukuda, Akihiko Mitsuke, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Masayuki Nakagawa, Shuichi Tatarano, Yasutoshi Yamada, Hideki Enokida |
| Source: | Molecular Oncology, Vol 18, Iss 9, Pp 2196-2211 (2024) |
| Publisher Information: | Wiley, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | erdefitinib, FASN, FGFR, HIF1α, metabolism, PHGDH, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine‐ and cisplatin‐resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine‐resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia‐inducible factor1α (HIF1α) expression, stimulating aerobic glycolysis. In gemcitabine‐resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain‐containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1α expression. PHGDH downregulation or inhibition in gemcitabine‐resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin‐resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl‐CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1α expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in vitro and in vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1878-0261 1574-7891 |
| Relation: | https://doaj.org/toc/1574-7891; https://doaj.org/toc/1878-0261 |
| DOI: | 10.1002/1878-0261.13684 |
| Access URL: | https://doaj.org/article/c2d8257116da49f8983df134c431822c |
| Accession Number: | edsdoj.2d8257116da49f8983df134c431822c |
| Database: | Directory of Open Access Journals |
| ISSN: | 18780261 15747891 |
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| DOI: | 10.1002/1878-0261.13684 |
| Published in: | Molecular Oncology |
| Language: | English |