the activation of b catenin signaling may result from ref 3 the downregulation of E cadherin at EMT. CD44 has Inhibitors,Modulators,Libraries been shown to be a downstream target of the b catenin signaling pathway. We found that elevated CD44 corre lated with the Inhibitors,Modulators,Libraries activation of b catenin in Twist overexpres sing cells. Interestingly, the activation of the b catenin pathway was not optimal, as treatment of Wnt3a can further induce the activation of b catenin and the induction of CD44, suggesting that EMT initiates and primes b catenin activation and this activation can be further synergized by the Wnt ligand from the tumor microenvironment. The expression of Twist also has been shown to activate the Akt pathway to promote migration, invasion and pacli taxel resistance.

The activation of Akt phosphorylated and suppressed GSK 3b, which is the major kinase for the phosphorylation of b catenin and Snail. The phos phorylation of these molecules by GSK 3b results in the consequent degradation of b catenin and Snail Inhibitors,Modulators,Libraries by E3 ligase b Trcp. Consistent with these findings, we discov ered that Akt was activated in Twist overexpressing cells, which lead to the phosphorylation and suppression of GSK 3b and resulted in the significant protein stabilization of b catenin and Snail in these cells. When E cadherin is downregulated at EMT, the released cytoplasmic b catenin is still subjected to GSK 3b mediated phosphorylaton and degradation. Thus, additional activation of the Akt path way is necessary to prevent this process and facilitates the nuclear translocation and activation of b catenin.

This speculation is consistent with the fact that EMT also cor relates with the presence of b catenin in the nucleus. Thus, activation of b catenin and Akt pathways is a syner gistic event at EMT and is critical for generating high grade invasive cells with stem cell like features. Second, our results suggest that targeting the b cate nin Inhibitors,Modulators,Libraries and Akt pathways can suppress the stem cell like properties associated with EMT. CSCs are often resistant to common drugs in vivo and in vitro when compared with the majority of the cancer cell popula tion, raising the question of whether traditional ther apy only debulks tumors, leaving CSCs to repopulate the original tumor and which results in disease recur rence.

Consistent with these findings, Cheng and her colleagues showed that the residual breast tumor cell populations that survived after conventional treatment Inhibitors,Modulators,Libraries were enriched for the subpopulation of cells with both tumor etc stem cell like features and EMT characteristics. Thus, more effective therapies will require the selective targeting of this crucial cell population. The elucidation of molecular pathways underlying the regu lation of CSC self renewal and survival is crucial to the success of this goal. In our study, we found that either the knockdown of b catenin expression or the suppres sion of the Akt pathway by wortmannin inhibited CD44 expression.