Boisvert-Adamo K, Aplin A E
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
Oncogene. 2006 Aug 10;25(35):4848-56. doi: 10.1038/sj.onc.1209493. Epub 2006 Mar 20.
A hallmark feature of cancer is resistance to anoikis, apoptosis induced when cells either lose contact with or encounter an inappropriate extracellular matrix. Melanoma is inherently associated with a high degree of resistance to apoptosis. Mutations in B-RAF are prevalent in melanoma and promote constitutive MEK-ERK1/2 signaling and cell transformation. Acquisition of B-RAF mutations correlates with vertical phase growth when melanoma cells invade into the dermis, a collagen-rich environment that also contains fibronectin matrix. In addition, alterations in phosphoinositide-3 kinase (PI-3 kinase) signaling that lead to activation of AKT are detected in advanced melanomas. Here we show that knockdown of B-RAF expression by siRNA or pharmacological inhibition of MEK rendered melanoma cells susceptible to anoikis. Furthermore, adhesion to fibronectin but not collagen protected melanoma cells from anoikis through a PI-3 kinase-dependent pathway. Therefore, melanoma cells require either B-RAF or PI-3 kinase activation for protection from anoikis. Notably, AKT signaling in melanoma cells is substrate specific. These findings demonstrate that melanoma cells utilize multiple signaling pathways to provide resistance to apoptosis.
癌症的一个标志性特征是对失巢凋亡具有抗性，失巢凋亡是细胞与细胞外基质失去接触或接触到不合适的细胞外基质时所诱导的细胞凋亡。黑色素瘤本质上与高度的凋亡抗性相关。B-RAF突变在黑色素瘤中普遍存在，并促进组成型MEK-ERK1/2信号传导和细胞转化。当黑色素瘤细胞侵入真皮（一种富含胶原蛋白且也含有纤连蛋白基质的环境）时，B-RAF突变的获得与垂直生长期相关。此外，在晚期黑色素瘤中检测到导致AKT激活的磷酸肌醇-3激酶（PI-3激酶）信号传导改变。在此我们表明，通过siRNA敲低B-RAF表达或对MEK进行药理学抑制可使黑色素瘤细胞易于发生失巢凋亡。此外，黏附于纤连蛋白而非胶原蛋白可通过PI-3激酶依赖性途径保护黑色素瘤细胞免于失巢凋亡。因此，黑色素瘤细胞需要B-RAF或PI-3激酶激活以保护其免于失巢凋亡。值得注意的是，黑色素瘤细胞中的AKT信号传导具有底物特异性。这些发现表明，黑色素瘤细胞利用多种信号通路来提供对凋亡的抗性。
