Scanlon K J, Ishida H, Kashani-Sabet M
Department of Medical Oncology, City of Hope Medical Center, Duarte, CA 91010.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11123-7. doi: 10.1073/pnas.91.23.11123.
This study examined the effects of suppressing c-fos oncogene expression on multidrug resistance (MDR). A2780S human ovarian carcinoma cells with resistance to actinomycin D were isolated and the resultant A2780AD cells exhibited the MDR phenotype. A hammerhead ribozyme designed to cleave fos RNA cloned into the pMAMneo plasmid was transfected into A2780AD cells. Induction of the ribozyme resulted in decreased expression of c-fos, as well as that of the MDR gene (mdr-1), c-jun, and mutant p53. The transformants displayed altered morphology and restored sensitivity to chemotherapeutic agents comprising the MDR phenotype. An anti-mdr ribozyme separately expressed in A2780AD cells efficiently degraded mdr-1 mRNA. However, reversal of the MDR phenotype by the anti-mdr ribozyme occurred one-fourth as rapidly as that induced by the anti-fos ribozyme. These results reinforce the central role played by c-fos in drug resistance through its participation in signal transduction pathways.
本研究检测了抑制c-fos癌基因表达对多药耐药性（MDR）的影响。分离出对放线菌素D具有抗性的A2780S人卵巢癌细胞，所得的A2780AD细胞表现出多药耐药表型。将设计用于切割克隆到pMAMneo质粒中的fos RNA的锤头状核酶转染到A2780AD细胞中。核酶的诱导导致c-fos以及多药耐药基因（mdr-1）、c-jun和突变型p53的表达降低。转化体表现出形态改变，并恢复了对构成多药耐药表型的化疗药物的敏感性。在A2780AD细胞中单独表达的抗mdr核酶有效地降解了mdr-1 mRNA。然而，抗mdr核酶诱导的多药耐药表型逆转速度仅为抗fos核酶诱导速度的四分之一。这些结果强化了c-fos通过参与信号转导途径在耐药性中所起的核心作用。
