25 - STAT signaling as a molecular target for cancer therapy

Summary

Introduction

STAT proteins (Signal Transducers and Activators of Transcripton) are latent cytoplasmic transcription factors that transmit signals from cytokines and growth factors directly to the nucleus. They become activated by tyrosine phosphorylation, which can be induced by growth-factor receptor kinases, cytokine-receptor-associated kinases or other non-receptor tyrosine kinases. Phosphorylated STAT proteins form activated dimers in the cytoplasm, translocate into the nucleus, where they bind to DNA and, in conjunction with other transcription factors, regulate gene expression. These unique properties of STAT proteins – transmitting signals from diverse cytokines and growth factors, which are often overly active in cancer, as well as regulating expression of numerous genes involved in cancer – position some of the STAT family proteins, especially STAT3, to be key mediators of oncogenesis and thus attractive targets for cancer therapy. It is important to recognize that the critical roles of STAT3 in cancer derive from the deregulation of normal physiological functions modulated by STAT3, including wound healing and immune responses to infection, as will become evident in this chapter.

There are seven members of the STAT protein family – STAT1 to STAT4, STAT6, and the closely related STAT5a and STAT5b proteins (Figure 25.1). The STAT family members share several key structural features, including the DNA binding, SH2, and transactivation domains (Figure 25.1). Despite similarities in their structures, the STAT family proteins have distinct functions, in some cases having opposite roles in many aspects of physiology and cancer. For example, STAT1, which is activated by interferon (IFN) stimulation, induces growth restraint, apoptosis, and tumor immune surveillance (1,2). In contrast, STAT3 and to some extent STAT5, promote tumor cell proliferation and survival, as well as suppress anti-tumor immune responses (3,4). Of particular interest for molecular targeting of this pathway are the underlying mechanisms by which STAT3 promotes oncogenesis through control of tumor cell proliferation, survival, angiogenesis, metastasis, and immune evasion.