Rosen K, Rak J, Jin J, Kerbel R S, Newman M J, Filmus J
Department of Cancer Biology Research Sunnybrook Health Science Centre S-218 Research Building 2075 Bayview Avenue Toronto Ontario M4N 3M5 Canada.
Curr Biol. 1998 Dec 3;8(24):1331-4. doi: 10.1016/s0960-9822(07)00564-7.
Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix [1] [2] [3]. In epithelial cells of the intestine and other organs, activated rasinduces resistance to anoikis [3] [4], but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours [5]. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells [6] [7]. Here, we show that activated rasinduces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis [8]. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of rasto downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.
失巢凋亡是正常上皮细胞因与细胞外基质脱离而诱导产生的一种程序性细胞死亡形式[1][2][3]。在肠道及其他器官的上皮细胞中，活化的Ras会诱导细胞对失巢凋亡产生抗性[3][4]，但直接参与执行或阻断失巢凋亡的凋亡机制的实际分子效应器尚未被鉴定出来。Bak是Bcl-2家族的促凋亡成员，在高比例的结直肠癌肿瘤中表达下调[5]。此外，Bak是正常肠上皮细胞凋亡的重要调节因子[6][7]。在此，我们表明活化的Ras会诱导大鼠和人肠上皮细胞中Bak的表达下调。这种由Ras诱导的Bak表达下调可被磷脂酰肌醇（PI）3激酶抑制剂抑制，PI 3激酶是一种已被证明与Ras诱导的失巢凋亡抗性有关的酶[8]。在Ras转化的大鼠肠上皮IEC-18细胞中异位表达Bak可抑制Ras诱导的失巢凋亡抗性，并显著降低其致瘤性。因此，我们得出结论，Ras下调Bak的能力以及随之而来的对失巢凋亡的抗性，是该癌基因在肠上皮细胞中转化能力的重要组成部分。
