Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

Abstract

Abstract: Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

Keywords: ovarian cancer; stat3; stat5.

Figure 1

Signal transducers and activators of transcription (STAT)3 and STAT5 signaling in epithelial ovarian cancer (EOC) and tumor microenvironment. Distinct families of cytokines such as Interleukins (IL-6,IL-11) and leukemia inhibitory factor (LIF) bind to their homodimeric cognate receptors IL-6R, IL-11R and LIFR respectively, and share a signal-transducing receptor gp130. Janus kinase (JAK) phosphorylate gp130 to enable docking and phosphorylation of STAT3 at Tyrosine (symbol Y or Tyr) residue 705. Tyrosine phosphorylation of STAT3 can also be mediated by activation of other oncogenic proteins including growth factor (GF)-mediated receptor Tyrosine kinase (RTK) activation, granulocyte colony-stimulating factor (G-CSF)-mediated activation, SRC and RAS/MEK/ERK pathway. Phosphorylated STAT3 dynamically undergo dimerization and nuclear translocation to trigger STAT3-mediated transcription of target genes. Binding of Prolactin to its receptor facilitate JAK-mediated phosphorylation of STAT5A and STAT5B at Tyr residue 694 and Tyr residue 699, respectively, leading to homodimerization or heterodimerization before nuclear translocation for target gene activation. STAT3 and STAT5 signaling in cancer cells release more cytokines into tumor microenvironment that generate a plethora of immune-compromising functions (highlighted in the main text). Figure created with Biorender.com.