Perryman L A, Blair J M, Kingsley E A, Szymanska B, Ow K T, Wen V W, MacKenzie K L, Vermeulen P B, Jackson P, Russell P J
Oncology Research Centre, Prince of Wales Hospital, Barker St., Randwick, NSW 2031, Australia.
Biochem Biophys Res Commun. 2006 Jul 7;345(3):1207-14. doi: 10.1016/j.bbrc.2006.05.020. Epub 2006 May 11.
This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous "take rate" in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.
本研究调查了三种特定的显性负性p53突变体（F134L、M237L和R273H）对LNCaP前列腺癌细胞致瘤作用的影响。突变型p53蛋白与NOD-SCID小鼠皮下“接种率”增加以及前列腺特异性抗原（PSA）产生增加有关。表达F134L和R273H的肿瘤生长比对照慢，且与坏死和凋亡减少有关，但与缺氧无关。有趣的是，表达M237L的肿瘤中缺氧水平增加。与对照相比，携带F134L的肿瘤中增殖较少，但这在统计学上不显著。与表达M237L的肿瘤或对照相比，表达F134L和R273H的肿瘤中血管生成减少。来自F134L肿瘤的条件培养基抑制正常人脐静脉内皮细胞的生长，但不抑制端粒酶永生化骨髓内皮细胞的生长。与表达其他突变体的肿瘤的上清液相比，F134L肿瘤的上清液显示出较低水平的血管内皮生长因子（VEGF）和内皮抑素。我们的结果支持这样一种可能性，即血管生成减少可能是表达F134L p53突变的肿瘤细胞生长速率降低的原因。
