The tumor suppressor p14ARF, encoded by the INK4a/ARF locus, is often disrupted in human cancers, p14ARF triggers cell cycle arrest and sensitizes cells to apoptosis in the presence of collateral signals. To investigate the role of p14ARF in chemotherapeutic drugs-induced apoptosis, p14ARF was overexpressed by stable transfection in human osteosarcoma cell lines, U2OS (p53-wt/p14ARF-null) and MG63 (p53-mt/p14ARF-null). The results showed that ectopic p14ARF sensitized both cell lines to cisplatin-induced cytotoxicity and apoptosis. This sensitization of cisplatin-induced apoptosis was associated with upregulation of p53, Bax and p21 in U2OS cells. Conversely, such a result was not observed in MG63 cells. Moreover, the sensitization of cisplatin-induced cytotoxicity in U2OS cells was unaltered by p53 siRNA. Together, we show here p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner. Proper combinations of p14ARF gene transfer and conventional chemotherapy may be a valuable strategy in human osteosarcoma treatment.

译文

由INK4a/ARF基因座编码的肿瘤抑制因子p14ARF通常在人类癌症中被破坏,p14ARF触发细胞周期停滞并在存在侧支信号的情况下使细胞对凋亡敏感。为了研究p14ARF在化疗药物诱导的细胞凋亡中的作用,p14ARF通过稳定转染在人骨肉瘤细胞系U2OS (p53-wt/p14ARF-null) 和MG63 (p53-mt/p14ARF-null) 中过表达。结果表明,异位p14ARF使两种细胞系对顺铂诱导的细胞毒性和凋亡敏感。顺铂诱导的凋亡的这种敏化与U2OS细胞中p53,Bax和p21的上调有关。相反,在MG63细胞中未观察到这样的结果。此外,p53 siRNA并未改变顺铂诱导的U2OS细胞细胞毒性的敏化作用。总之,我们在这里显示p14ARF以p53-independent的方式使人骨肉瘤细胞对顺铂诱导的凋亡敏感。p14ARF基因转移和常规化疗的适当组合可能是人类骨肉瘤治疗的有价值的策略。

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