TAT3 activity and tumor growth. The higher AZD1480 the level of STAT3 in a tumor cell line, the more susceptible it is to STAT3 inhibition. Despite the testing of a number of different STAT3 inhibitors, their overall anti tumor effects have not been overly impressive. One explanation is that most of currently available STAT3 inhibitors target the conventional STAT3 pathway, i. e. STAT3 tyrosine phosphorylation, dimerization and DNA binding. This pathway, however, may not be the only mechanism through which STAT3 promotes tumorigenesis. For example, forced expression of a nonphosphorylatable STAT3 variant can mimic some STAT3 dependent functions in tumorigenesis. To address this possibility, STAT3 ablation via systemic administration of a validated antisense oligonucleotide was recently tested in mouse tumor models.
The Stat3 antisense oligonucleotide significantly reduced STAT3 protein amounts and inhibited cell proliferation and tumorigenic growth of several human HCC cell lines transplanted into mice. A similar anti tumor effect of Stat3 antisense oligonucleotides was shown in a mouse lymphoma model. BMS 794833 Effective inhibition of tumorigenic growth of many different types of cancernpg cells transplanted into mice was observed upon treatment with AZD1480, a highly specific JAK2 inhibitor. Crosstalk between IKK/NF ?B and STAT3 in liver cancer NF ?B and STAT3 each control the expression of a large number of downstream genes that control cell proliferation, survival, stress responses and immune functions. Some of the target genes for NF ?B and STAT3 overlap and in addition, the two transcription factors are engaged in both positive and negative crosstalk.
In mouse DEN model, DEN induced hepatocyte death results in release of IL 1 which activates NF ?B signaling in Kupffer cells, which produce a panel of cytokines and growth factors, including IL 6. IL 6 released by Kupffer cells activates STAT3 in hepatocytes and STAT3 activated genes are critical for compensatory hepatocyte proliferation and liver tumorigenesis. However, more recently we found that the two transcription factors are also engaged in negative crosstalk within HCC cells. NF ?B activation results in increased expression of proteins, such as ferritin heavy chain and superoxide dismutase 2 that have an anti oxidant function that prevents excessive ROS accumulation.
Inactivation of IKK in HCC cells or hepatocytes favors the accumulation of ROS which oxidize the catalytic cysteine of various protein tyrosine phosphatases, including SHP1 and SHP2, the phosphatases that dephosphorylate STAT3 and JAK2. Oxidation of SHP1 and SHP2 results in loss of their catalytic activity and accumulation of phosphorylated and activated JAK2 and STAT3, which stimulate the proliferation and tumorigenic growth of NF ?B deficient HCC. Treatment of mice bearing IKK deficient tumors with an anti oxidant restores SHP1/2 activity, reduces JAK2 and STAT3 phosphorylation and inhibits tumor growth. More recently, the loss of IKK in neutrophils was also found to result in activation of STAT3, which enhances the survival and proliferation of NF ?B deficient neutrophils. Not only NF ?B can affect STAT3 activity, STAT3 was also found to contribute to NF ?B activation. Activated STAT3 in cancer cells is able to bind RelA/p65 in the