Department of Pharmacology, Shanghai Institute of Materia Medica, China Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Mol Cancer. 2010 Jan 14;9:7. doi: 10.1186/1476-4598-9-7.
Apoptosis caused by inadequate or inappropriate cell-matrix interactions is defined as anoikis. Although transformed cells are known to be anoikis-resistant, the underlying mechanisms have not been well understood. We investigated the mechanisms of anoikis resistance of tumor cells.
We observed that cell aggregation in suspension promoted cell survival and proliferation. We demonstrated a correlation between tumor cell aggregation in suspension and cell growth in soft agar. Analysis of tyrosine kinase-mediated cell survival and growth signaling pathways revealed increased levels of tyrosine-phosphorylation of PECAM-1 and Pyk2 in cell aggregates. We also showed that PECAM-1 and Pyk2 physically interact with each other, and that PECAM-1 carrying a deletion of exons 11-16 could no longer bind to Pyk2. Furthermore, RNA interference-mediated reduction of Pyk2 and PECAM-1 protein levels reduced cell aggregation and inhibited the growth of tumor cells in soft agar.
The data demonstrated that Pyk2 and PECAM-1 were critical mediators of both anchorage-independent growth and anoikis resistance in tumor cells.
由于细胞-基质相互作用不足或不适当而导致的细胞凋亡被定义为失巢凋亡。虽然已知转化细胞对失巢凋亡具有抗性，但潜在的机制尚未得到很好的理解。我们研究了肿瘤细胞失巢凋亡抗性的机制。
我们观察到在悬浮液中细胞聚集促进了细胞的存活和增殖。我们证明了肿瘤细胞在悬浮液中的聚集与软琼脂中的细胞生长之间存在相关性。分析酪氨酸激酶介导的细胞存活和生长信号通路表明，在细胞聚集体中 PECAM-1 和 Pyk2 的酪氨酸磷酸化水平升高。我们还表明 PECAM-1 和 Pyk2 相互物理作用，并且携带外显子 11-16 缺失的 PECAM-1 不再与 Pyk2 结合。此外，RNA 干扰介导的 Pyk2 和 PECAM-1 蛋白水平的降低减少了细胞聚集并抑制了肿瘤细胞在软琼脂中的生长。
数据表明 Pyk2 和 PECAM-1 是肿瘤细胞中锚定非依赖性生长和失巢凋亡抗性的关键介质。
