Coll Mariano Loza, Rosen Kirill, Ladeda Virginia, Filmus Jorge
Sunnybrook and Women's College Health Science Center, Division of Molecular and Cell Biology, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Oncogene. 2002 Apr 25;21(18):2908-13. doi: 10.1038/sj.onc.1205388.
Acquisition of resistance to anoikis (detachment-induced apoptosis) is considered to be a requirement for transformed intestinal epithelial cells to invade surrounding tissues and metastasize to distant organs. Increased Src kinase activity, which is a feature of a large proportion of colorectal cancers, has been identified as one of the factors that can contribute to anoikis resistance. However, the molecular mechanism by which high levels of Src activity contribute to anoikis resistance in intestinal epithelial cells is unknown. Here we show that high Src activity confers resistance to anoikis in intestinal epithelial cells, at least in part, by inducing Bcl-xL overexpression, and that this induction is mediated by the MEK/MAPK pathway. Based on the findings reported here, and on our previous study showing that Bcl-xL plays a critical role in ras-induced resistance to anoikis, we propose that the increased Bcl-xL levels found in colorectal cancers play a significant role in the induction of resistance to anoikis during the progression of this disease.
获得对失巢凋亡（脱离诱导的凋亡）的抗性被认为是转化的肠上皮细胞侵入周围组织并转移至远处器官的必要条件。Src激酶活性增加是大部分结直肠癌的一个特征，已被确定为可导致失巢凋亡抗性的因素之一。然而，高水平的Src活性导致肠上皮细胞失巢凋亡抗性的分子机制尚不清楚。在这里，我们表明，高Src活性至少部分地通过诱导Bcl-xL过表达赋予肠上皮细胞对失巢凋亡的抗性，并且这种诱导是由MEK/MAPK途径介导的。基于本文报道的研究结果以及我们之前的研究表明Bcl-xL在ras诱导的失巢凋亡抗性中起关键作用，我们提出在结直肠癌中发现的Bcl-xL水平升高在该疾病进展过程中对失巢凋亡抗性的诱导中起重要作用。
