Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer

Abstract

Prostate cancer is the most common non-cutaneous cancer in Western males. The majority of prostate cancer fatalities are caused by development of castration-resistant growth and metastatic spread of the primary tumor. The average duration of the response of primary prostate cancer to hormonal ablation is less than 3 years, and 75% of prostate cancers in the United States progress to castration-resistant disease. The existing pharmacological therapies for metastatic and/or castration-resistant prostate cancer do not provide significant survival benefit. This review summarizes the importance of transcription factor Stat5 signaling in the pathogenesis of prostate cancer and discusses the molecular basis of Stat5a/b inhibition as a therapeutic strategy for prostate cancer.

Figure 1. The members of Stat family of transcription factors

A. Chromosomal location in human, sequence identity between human and mouse Stats and the major structural features and phosphorylation sites. B. Schematic Stat5a domains and specific amino acids mediating important functions. Glycosylation of threonine 92 (T92) is crucial for interaction with p300/CREB-binding protein. Phosphorylation of tyrosine 694 (Y694) is essential for Stat5a activation. Mutation of serine 710 to phenylalanine (S710F) confers constitutive activation to Stat5a (gain of fuction). Phosphorylation of serine 725 has an impact on signal duration.

Figure 2. The canonical Prolactin (Prl)-Jak2-Stat5a/b signaling pathway

Prl binding brings the PrlR-associated Jak2 molecules into close proximity and subsequent activation. Cytoplasmic Stat5a/b proteins are recruited to the activated Prl-receptor-Jak2 complex, and Jak2 phosphorylates tyrosine residues Y694 and Y699 of Stat5a and Stat5b, respectively, leading them to homo- or heterodimerize through a phosphotyrosine SH2 domain interaction. Phosphorylated Stat5a/b dimers translocate from the cytoplasm into the nucleus, where they bind to DNA to regulate transcription.

Figure 3. Interaction of Stat5a/b and androgen receptor (AR) signaling pathways in prostate cancer cells

Binding of Prl leads to Prl-receptor (PrlR) dimerization and activation of Jak2 proteins pre-associated with the cytoplasmic domains of PrlR. Cytoplasmic Stat5a/b are recruited to the activated PrlR-Jak2 complex, Stat5a/b is phosphorylated on a conserved tyrosine residue in the C-terminus of Stat5a/b by Jak2 resulting in Stat5 dimerization. Ligand binding to the AR leads to its dissociation from the heat shock proteins (HSPs) and dimerization. Liganded AR physically interacts with Stat5a/b in prostate cancer cells. Liganded AR and active Stat5a/b promote nuclear translocation and transcriptional activity of each other. Both AR and Stat5 signaling pathways are critical regulators of growth, viability and apoptosis of prostate cancer cells.