Sensitization of cervical cancer cell lines to low-dose radiation by retinoic acid does not require functional p53.
Sensitization of cervical cancer cell lines to low-dose radiation by retinoic acid does not require functional p53.
复制标题
视黄酸使宫颈癌细胞系对低剂量辐射敏感不需要功能性 p53。
DOI：
10.1016/j.ygyno.2004.12.034
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发表时间：
2005
影响因子：
4.7
通讯作者：
Benbrook,DorisM
中科院分区：
文献类型：
--
作者：
Tillmanns,ToddD;Kamelle,ScottA;Guruswamy,Suresh;Gould,NatalieS;Rutledge,TeresaL;Benbrook,DorisM
目前宫颈癌的治疗包括放射治疗。维甲酸（RA）可增加宫颈癌细胞对放射线的敏感性。这种致敏的机制可能不涉及p53蛋白，因为存在于大多数宫颈癌中的人乳头瘤病毒（HPV）E6蛋白促进p53降解。本研究的目的是确定p53是否参与RA放射增敏的机制。在各种实验条件下，使用克隆形成，库尔特计数器，电泳迁移率变动（EMSA）和p53诱导基因的多探针RNA酶保护试验。（5 μM 9-cis-RA）放射增敏含有HPV降解的p53的SiHa和CC-1细胞系，但不放射增敏HPV阴性且含有野生型p53的SW 962细胞系，也不放射增敏C33 a细胞系，其含有突变型p53（R273 C）。突变型p53（R273 H）在SiHa细胞中的表达增加了生长速率，但在临床相关剂量下并不能阻止RA诱导的分化或放射增敏。用pifithirin α抑制p53反式激活并不能阻止SiHa在5戈伊的RA放射增敏作用。RA抑制对照组和照射组SiHa细胞c-fos mRNA的表达，但不抑制bcl-xL、p53、GADD 45、p21、bax、bcl-2和mcl-1 mRNA的表达。
OBJECTIVECurrent therapy for cervical cancer includes radiation therapy. Retinoic acid (RA) can increase the sensitivity of cervical cancer cell lines to radiation. The mechanism of this sensitization may not involve the p53 protein because the human papillomavirus (HPV) E6 protein, which is present in the majority of cervical cancers, promotes p53 degradation. The objective of this study was to determine if p53 is involved in the mechanism of RA radiosensitization.METHODSThe effects of radiation on cervical (SiHa, CC-1, and C33a) and vulvar (SW962) cancer cell lines under various experimental conditions were evaluated using clonogenic, Coulter Counter, electrophoretic mobility shift (EMSA) and a multi-probe RNase protection assay of p53-inducible genes.RESULTSRA (5 μM 9-cis-RA) radiosensitized the SiHa and CC-1 cell lines that contain HPV-degraded p53, but did not radiosensitize the SW962 cell line, which is HPV negative and contains wild-type p53, nor the C33a cell line, which contains mutant p53 (R273C). Expression of mutant p53 (R273H) in SiHa cells increased the growth rate, but did not prevent RA-induced differentiation or radiosensitization at clinically relevant doses. Inhibition of p53 transactivation with pifithirin α did not prevent RA radiosensitization of SiHa at 5 Gy. RA repressed c-fos mRNA expression in control and irradiated SiHa cultures, but did not repress bcl-xL, p53, GADD45, p21, bax, bcl-2, or mcl-1 mRNA expression.CONCLUSIONSThe mechanism of RA radiosensitization does not require functional p53 and may involve c-fos in cervical cancer cell lines.