Loss of the cystine/glutamate antiporter in melanoma abrogates tumor metastasis and markedly increases survival rates of mice
| Autor: | Shiro Bannai, Nahoko Kakihara, Regina Feederle, José Pedro Friedmann Angeli, Mio Domon, Katalin Buday, Mami Sato, Futoshi Okada, Ami Suzuki, Bettina Proneth, Kunishige Onuma, Remi Hino, Mitsuhiko Osaki, Yusuke Kanda, Marcus Conrad, Ryosuke Kusumi, Shun Hasegawa, Junichi Hamada, Hideyo Sato |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Amino Acid Transport System y+ SLC7A11 Metastasis Gene Knockout Techniques Mice 03 medical and health sciences 0302 clinical medicine Cell Movement In vivo Cell Line Tumor medicine Animals Humans Melanoma System X(c)(-) Tumor Growth Neoplasm Metastasis Cell Proliferation biology Chemistry Cancer medicine.disease In vitro Gene Expression Regulation Neoplastic Survival Rate Endothelial stem cell Oncology Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research Female Neoplasm Transplantation |
| Zdroj: | Int. J. Cancer 147, 3224-3235 (2020) |
| ISSN: | 1097-0215 0020-7136 |
| Popis: | The cystine/glutamate antiporter, system x(c)(-), is essential for the efficient uptake of cystine into cells. Interest in the mechanisms of system x(c)(-)function soared with the recognition that system x(c)(-)presents the most upstream node of ferroptosis, a recently described form of regulated necrosis relevant for degenerative diseases and cancer. Since targeting system x(c)(-)hold the great potential to efficiently combat tumor growth and metastasis of certain tumors, we disrupted the substrate-specific subunit of system x(c)(-), xCT (SLC7A11) in the highly metastatic mouse B16F10 melanoma cell line and assessed the impact on tumor growth and metastasis. Subcutaneous injection of tumor cells into the syngeneic B16F10 mouse melanoma model uncovered a marked decrease in the tumor-forming ability and growth of KO cells compared to control cell lines. Strikingly, the metastatic potential of KO cells was markedly reduced as shown in several in vivo models of experimental and spontaneous metastasis. Accordingly, survival rates of KO tumor-bearing mice were significantly prolonged in contrast to those transplanted with control cells. Analyzing the in vitro ability of KO and control B16F10 cells in terms of endothelial cell adhesion and spheroid formation revealed that xCT expression indeed plays an important role during metastasis. Hence, system x(c)(-)emerges to be essential for tumor metastasis in mice, thus qualifying as a highly attractive anticancer drug target, particularly in light of its dispensable role for normal life in mice. |
| Databáze: | OpenAIRE |
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