STAT3 downregulation after FLLL32 treatment occurred through the ubiquitin prot

STAT3 is activated in response to several cytokines and growth factors, including IL 6, epidermal growth factor, and interferon a, STAT3 is also weakly activated in response to other cytokines, including IFNg. Activation of STAT3 results from the phosphorylation of tyrosine 705, mediated by Janus Kinases, which are associated ARN-509 956104-40-8 to cytokine recep tors, and also by the Src and Abelson families of protein tyrosine kinases. STAT3 is also phosphory lated on serine 727, sometimes resulting in its activa tion. Following phosphorylation, STAT3 dimerizes and enters the nucleus by interacting with nuclear import proteins of the karyopherin importin family. The importins interact with nuclear localization signals, one of which is located within the DNA binding domain of STAT3 and is thought to be the most efficient.<br><br> Once in the nucleus, STAT3 activates the transcription of its target genes, including cyclin D1, survivin, VEGF, c myc, Bcl xL, and AUY922 747412-49-3 Bcl2. Once released from its DNA targets, STAT3 is dephosphorylated in the nucleus and exported to the cytoplasm by a CRM1 dependent process. STAT3 has been described as a key regulator of cell survival and proliferation, its constitutive activation has been observed in many human tumors, including colon, breast, lung, pancreas and prostate cancers, melanoma, head and neck squamous carcinoma, multiple myeloma, mantle cell lymphoma, and glioma. In addition, substituting amino acids located at the STAT3 dimer interface for cysteines yielded a stabilized STAT3 dimer that was able to induce a pseudotransformed phenotype.<br><br> Thus, its constitutive activation in tumor cells points to STAT3 as a valuable target for attacking tumor cells. Alisertib 臨床試験 Furthermore, despite its essential role in development, STAT3 is not essential for the func tioning of mature cells. Some STAT3 inhibitors are not specific, such as curcumin. In contrast, Stattic, which prevents STAT3 dimerization by specifically interacting with its SH2 domain, is highly specific, and efficiently induces tumor cell death. Despite its frequent involvement in cancer, which makes it a highly valuable target for inducing tumor cell death, STAT3 still lacks more specific inhibitors. Besides the SH2 domain, another potential target for highly selective STAT3 inhibitors is its DBD, since it selectively recog nizes and binds DNA motifs in target genes.<br><br> Decoy oli gonucleotides containing the TFs DNA binding consensus sequences selectively inhibit them by binding to the DBD. They can induce, in vitro, the death of tumor cells whose growth depends on these TFs. This has notably been shown for several TFs, including NF B and STAT3. STAT3 decoy ODN efficiently induced cell death in mouse xenografts of a head and neck squamous cell car cinoma. One limitation of STAT3 decoy ODN is that despite the different functions of STAT1 and STAT3 in the cell, they recognize very similar DNA tar gets, with the result that STAT3 decoy ODN can inhibit either one or the other. For example, in the colon carcinoma cell line SW 480, the constitutive acti vation of STAT3 contributes to cell survival, its inhibi tion by STAT3 decoy ODN induces cell death. However, the ODN also blocks IFNg mediated cell death through STAT1 activation in the same cell line.