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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >LACK OF FUNCTIONAL RETINOBLASTOMA PROTEIN MEDIATES INCREASED RESISTANCE TO ANTIMETABOLITES IN HUMAN SARCOMA CELL LINES
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LACK OF FUNCTIONAL RETINOBLASTOMA PROTEIN MEDIATES INCREASED RESISTANCE TO ANTIMETABOLITES IN HUMAN SARCOMA CELL LINES

机译：功能性视网膜母细胞蛋白的缺乏介导了人类肉瘤细胞株对抗代谢物的抗性增强

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Growth inhibition assays indicated that the IC50 values for methotrexate (MTX) and 5-fluorodeoxyuridine (FdUrd) in HS-18, a liposarcoma cell line lacking retinoblastoma protein (pRB), and SaOS-2, an osteosarcoma cell line with a truncated and nonfunctional pRB, were 10- to 12-fold and 4- to 11-fold higher, respectively, than for the HT-1080 (fibrosarcoma) cell line, which has wild-type pRB. These Rb--/- cell lines exhibited a 2- to 4-fold increase in both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzyme activities as well as a 3- to 4-fold increase in mRNA levels for these enzymes compared to the HT-1080 (Rb-+/+) cells. This increase in expression was not due to amplification of the DHFR and TS genes. Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells. In contrast, there was no significant difference in growth inhibition among these cell lines for the nonantimetabolites VP-16, cisplatin, and doxorubicin. A gel mobility-shift assay showed that parental SaOS-2 cells had increased levels of free E2F compared to the Rb-reconstituted SaOS-2 cells. These results indicate that pRB defective cells may have decreased sensitivity to growth inhibition by target enzymes encoded by genes whose transcription is enhanced by E2F proteins and suggest mechanisms of interaction between cytotoxic agents and genes involved in cell cycle progression. [References: 61]
机译：生长抑制试验表明，HS-18（缺少视网膜母细胞瘤蛋白（pRB）的脂肪肉瘤细胞系）和SaOS-2（截短且无功能的骨肉瘤细胞系）的甲氨蝶呤（MTX）和5-氟脱氧尿苷（FdUrd）的IC50值与具有野生型pRB的HT-1080（纤维肉瘤）细胞系相比，pRB分别高10至12倍和4至11倍。与这些酶相比，这些Rb-/-细胞系的二氢叶酸还原酶（DHFR）和胸苷酸合酶（TS）酶活性均提高了2至4倍，而mRNA水平则提高了3至4倍HT-1080（Rb-+ / +）细胞。表达的增加不是由于DHFR和TS基因的扩增。在SaOS-2细胞的Rb转染子中，MTX和FdUrd的生长抑制作用增加，DHFR和TS活性及表达相应降低。相反，在这些细胞系中，对于抗代谢物VP-16，顺铂和阿霉素的生长抑制没有显着差异。凝胶迁移率迁移分析表明，与Rb重组SaOS-2细胞相比，亲本SaOS-2细胞的游离E2F水平升高。这些结果表明，pRB缺陷细胞对由其转录被E2F蛋白增强的基因编码的靶酶抑制生长的敏感性可能降低，并暗示了细胞毒性剂与参与细胞周期进程的基因之间相互作用的机制。 [参考：61]

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