Second, TGF-β1 has a broad and multifunctional role because of this intricate system of components. Besides Smad-mediated transcription, TGF-β1 could also activate other signaling Selleckchem Tipifarnib cascades, including MAPK, Erk, JNK and other yet-to-be-determined 17-AAG purchase Smad-independent pathways [33]. Although this convergence of Smad-dependent and Smad-independent pathways in TGF-β family signaling can result in cooperativity, these pathways may also counteract each other, thereby enabling CNE2 cells to escape the tumor-suppressor effects of TGF-β1 and becoming resistant to TGF-β1-induced growth inhibition. Third, although it is generally accepted that TGF-β1 acts as a tumor suppressor through its ability to

induce growth arrest at early stages, TGF-β1 can also act as a tumor promoter. Numerous studies have demonstrated that most cancer cells secrete larger amounts of TGF-β1 than their normal cell counterparts, and this overexpression is strongest in the most advanced stages of malignancies including nasopharyngeal carcinoma [6, 7]. These malignancies can subvert TGF-β1 for their own purposes of

survival, promoting angiogenesis, cell spreading, immunosuppression, tumor cell invasion and metastasis at late stages of tumorigenesis [34–37]. The CNE2 cell Selleckchem NU7441 is a late-phage differentiation NPC cell line, so TGF-β1 is likely to serve as a tumor promoter rather than a tumor suppressor in CNE2 cells. Lastly, although the mechanism by which TGF-β1 switches its growth inhibitory effect into growth stimulatory effect is

not well understood, TGF-β1 has been shown to increase the production of several mitogenic growth factors including TGF-α, FGF and EGF [38]. In addition, prolonged experimental exposure to high levels of TGF-β has been demonstrated to promote neoplastic transformation of intestinal epithelial cells, and TGF-β1 stimulates the proliferation and invasion Etoposide molecular weight of poorly differentiated and metastatic colon cancer cells [39, 40]. Currently, less is known regarding the role of TGF-β1 and the TGF-β/Smad signaling pathway in the CNE2 cell, however, one study by using DNA microarray analysis demonstrates that the genes of TβR-I and TβR-II are upregulated in CNE2 cells [41], which is consistent with the our observation that TβR-II is expressed normally in CNE2 cells (Figure 2, 3). In summary, an important issue addressed in this study is that CNE2 cells are not sensitive to growth suppression by TGF-β, but the TGF-β/Smad signaling transduction is functional. Further work is necessary to delineate a more detailed spectrum of the TGF-β/Smad signaling pathway, as well as understanding its crosstalk with other signaling pathways in CNE2 cells. By analogy to the situation in nasopharyngeal carcinoma, the components of the TGF-β/Smad signaling pathway may be a new target in the chemoprevention and chemotherapy of nasopharyngeal carcinoma.