New and Old Functions of STAT3: A Pivitol Target for Individualized Treatment of Cancer

Abstract

Signal transducers and activators of transcription (STAT) regulate a plethora of cytokine responses. Recently, aberrant signaling by STAT proteins has been demonstrated to play important roles in the pathogenesis of many neoplasms, by promoting cell cycle progression and survival, stimulating angiogenesis, and impairing immunological responses and tumor surveillance. We have developed genetic tools to evaluate STAT-dependent malignancy and showed that survival and growth of lymphoid malignancies requires expression of STAT3. In contrast, loss of STAT3 in normal cells does not impair their growth or survival; but in spite of this apparent dispensability of STAT3, STAT3-null fibroblasts are resistant to transformation by a variety of oncogenes. The precise molecular mechanisms responsible for the tumorigenic activity of STAT3 have been only partially elucidated. While the tyrosine phosphorylation of STAT3, which is indicative of its signal-dependent activation, is a common occurrence in tumors, and appears to play a crucial role in some malignancies, a variety of new data suggest that it can be dispensable under some circumstances and STAT3 can participate in transformation through novel and non-canonical mechanisms. The discovery and dissection of non-canonical modes of STAT3 action will open new avenues for the design of effective therapeutics capable of neutralizing the tumorigenic properties of this molecule.

The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1

“…4 In the present study, we investigated the activity of the novel multitargeted TKI EXEL-0862 against the human FIP1L1-PDGFR-a-expressing cells to determine whether this compound might be a potential candidate for clinical development in patients with HES. We documented that 24,27 and Erk1/2 enhances the activity of anti-apoptotic Bcl-2 family members, such as Bcl-2 and Mcl-1. 28,29 Collectively, our data suggested that EXEL-0862 decreased proliferation and induced apoptosis through ablation of STAT3 and Erk1/2 phosphorylation.…”

NF-κB and STAT3 – key players in liver inflammation and cancer

“…Given this strict dependence on STAT3 for survival, it is puzzling to find that a few tumors can still develop in the complete absence of STAT3 in both the DEN-induced HCC model and in NPM-ALK transgenic mice [65,79]. It is plausible that an alternative pathway can be activated in STAT3-null tumors but this pathway is hardly active in the presence of STAT3 [78].…”

“…Using such conditional STAT3 knockout mice, it has been shown that STAT3 is required for tumorigenesis in mouse skin [75], intestine [76,77] and liver [65]. Such results left little doubt that STAT3 is a critical oncogenic transcription factor and an attractive target for cancer therapy [78].…”

Crif1 is a novel transcriptional coactivator of STAT3

“…Considerable effort is currently being focused on finding compounds capable of inhibiting various aspects of STAT3 function, through the inhibition of phosphorylation, dimerization, and DNA binding of STAT3 (Inghirami et al, 2005). SOCS1 reportedly suppressed STAT3 activation in a subset of hepatocellular carcinoma cells with STAT3 phosphorylated by JAKs (Yoshikawa et al, 2001).…”