Ehrhardt H, Häcker S, Wittmann S, Maurer M, Borkhardt A, Toloczko A, Debatin K-M, Fulda S, Jeremias I
Department of Oncology/Hematology, Dr von Haunersches Kinderspital, München, Germany.
Oncogene. 2008 Jan 31;27(6):783-93. doi: 10.1038/sj.onc.1210666. Epub 2007 Jul 16.
Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.
凋亡抗性在癌症的发生和发展中起着至关重要的作用，是抗癌治疗失败的主要原因，例如，它是由促凋亡细胞内信号分子如半胱天冬酶 - 8的下调所引起的。我们发现细胞毒性药物甲氨蝶呤（MTX）和5-氟尿嘧啶（5-FU）都能够通过p53介导的半胱天冬酶 - 8上调使耐药肿瘤细胞对凋亡诱导敏感。半胱天冬酶 - 8信使核糖核酸和蛋白质表达的增加使肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的增殖失活，并恢复了对TRAIL诱导凋亡的敏感性，而这种敏感性被p53诱饵寡核苷酸、p53短发夹RNA和半胱天冬酶 - 8短发夹RNA的转染所抑制。在一组广泛的半胱天冬酶 - 8下调的肿瘤细胞系以及急性白血病儿童的TRAIL耐药原发性肿瘤细胞中均发现了半胱天冬酶 - 8的上调和对TRAIL诱导凋亡的敏感性。综上所述，我们已确定半胱天冬酶 - 8是一种受细胞毒性药物调节的重要p53靶基因。这些发现突出了一种新的药物诱导的生理凋亡途径调节，这可能与数十年来在白血病和实体瘤中使用MTX和5-FU成功进行抗癌治疗有关。
