TGF-β inhibits Akt-induced transformation in intestinal epithelial cells
TGF-β inhibits Akt-induced transformation in intestinal epithelial cells
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DOI：
10.1016/j.surg.2006.05.006
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发表时间：
2006-08-01
期刊：
影响因子：
3.8
通讯作者：
Ko, Tien C.
中科院分区：
文献类型：
--
作者：
Cao, Yanna;Deng, Chunyan;Ko, Tien C.
背景在结直肠癌发生的早期阶段，磷脂酰肌醇3-激酶（PI 3 K）/Akt通路被激活，使转化细胞能够在没有锚定细胞外基质的情况下存活和生长。转化生长因子β（TGF-β）是结肠中重要的肿瘤抑制因子，并且在结直肠癌发生的后期阶段失活。本研究的目的是确定TGF-β是否抑制Akt诱导的肠上皮细胞的锚定非依赖性生长和抗失巢凋亡。用含有pLXSN-mAkt的逆转录病毒感染大鼠肠上皮细胞（RIE-1），并选择三个独立的克隆。通过软琼脂中的集落形成和超低附着平板中的细胞计数来检查锚定非依赖性生长。用Annexin V染色分析失巢凋亡。RIE-1/mAkt的所有三个克隆都在软琼脂中形成了菌落，但TGF-β可以减少这些菌落。TGF-β诱导的失巢凋亡和一般半胱天冬酶抑制剂zVAD-氟甲基酮的治疗阻断了TGF-β介导的集落形成减少。TGF-β通过增强失巢凋亡减弱Akt诱导的RIE-1细胞的锚定非依赖性生长我们的数据表明，一种新的肿瘤抑制活性的TGF-β，并提供所需的PI 3 K/Akt通路的激活和随后的失活的TGF-β信号在结直肠癌发生过程中的分子理由。
Background. During the early stages of colorectal carcinogenesis, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated, enabling the transformed cells to survive and grow in the absence of anchorage to extracellular matrix. Transforming growth factor beta (TGF-beta) is an important tumor suppressor in the colon, and it is inactivated during later stages of colorectal carcinogenesis. The purpose of this study was to determine whether TGF-beta inhibits Akt-induced anchorage-independent growth and resistance to anoikis in gut epithelial cells.Methods. Rat intestinal epithelial cells (RIE-1) were infected with a retrovirus containing pLXSN-mAkt, and three independent clones were selected. Anchorage-independent growth was examined by colony formation in soft agar and cell counting in ultralow attachment plates. Anoikis was analyzed with the use of Annexin V staining.Results. All three clones of RIE-1/mAkt formed colonies in soft agar, which were decreased by TGF-beta. TGF-beta induced anoikis and treatment with a general caspase inhibitor, zVAD-fluoromethyl ketone, blocked TGF-beta-mediated decrease in colony formation.Conclusions. TGF-beta attenuated Akt-induced anchorage-independent growth in RIE-1 cells in pail by enhancing anoikis. Our data demonstrate a novel tumor-suppressor activity of TGF-beta and provide the molecular justification for the required activation of the PI3K/Akt pathway and the subsequent inactivation of TGF-beta signaling during colorectal carcinogenesis.