Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication

Abstract

Signal Transducer and Activator of Transcription (STAT) pathway is connected upstream with Janus kinases (JAK) family protein and capable of integrating inputs from different signaling pathways. Each family member plays unique functions in signal transduction and crucial in mediating cellular responses to different kind of cytokines. STAT family members notably STAT3 and STAT5 have been involved in cancer progression whereas STAT1 plays opposite role by suppressing tumor growth. Persistent STAT3/5 activation is known to promote chronic inflammation, which increases susceptibility of healthy cells to carcinogenesis. Here, we review the role of STATs in cancers and inflammation while discussing current therapeutic implications in different cancers and test models, especially the delivery of STAT3/5 targeting siRNA using nanoparticulate delivery system.

Keywords: STAT transcription factors; STAT3; cancer; inflammation; therapeutic implication.

Figure 1

Domain structures of the STAT family members. N-terminal is required for protein interactions, SH-2 domains are required for dimerization, both the N-terminal and SH-2 domains mediated homo or heterodimer formation. Coiled-coil domains are required as a nuclear localization signal for activation. Y-S within the C-terminal are the phosphorylation sites.

Figure 2

Activated STAT3/5 signaling pathway by IL-6 receptor, Prolactin (PRL) receptor, VEGF Receptor, EGF Receptor, and IL-10 receptor. STAT3 and STAT5 are activated through tyrosine phosphorylation, then the STAT3/5 moomer undergoes dimerization and translocated into the nucleus. In the nucleus, STAT3/5 dimers binds to the promoter region or γ-interferon activation sequence (GAS) of target genes with co-factors, such as Nuclear Factor Kappa (NF-κB), Hypoxia-inducible factor 1-alpha (HIF-1α), protein kinase B (Akt), and p300 to transcript genes related to inflammation, proliferation, migration, and survival. NF-κB is activated through the phosphorylation of Inhibitor of kappa (IκB-α). PRLR activate Mitogen-activated protein kinase (MAPK) and Phosphoinosite 3-kinase (PI3K) pathways to produce co-regulators that are required for expression of certain STAT5-related genes.

Figure 3

STAT3 siRNA delivery using Polyethyleneimine (PEI), Ploy L-co-glycolic Acid (PLGA), and Inorganic compound, such as gold nanoparticles and Hydroxyapatite (HAP) nanoparticles to target ovarian cancer cells, malfunctioned dendritic cells, lung cancer cells, melanoma cancer cells, and prostate cancer cells. STAT3 siRNA delivery using polypeptides, solid lipid nanoparticles, polysaccharide, and aptamer. Poly (ethylene glycol)-b-poly (L-lysine)-b-poly (L-leucine) (PEG-PPL-PLLeu) is used to target melanoma cells while Triethylamine hybrid nanoparticles (tLypl-hNPs) targets Regulatory T-cells. Legumin-targeting strategy is employed to targeting breast cancer cells using encapsulated hydrocarbon carrier. Anionic charged siRNA co-assembled with polysaccharide hyaluronan-sulfate (HAS) to target mouse colon cancer cells. Gint4.T-STAT3 was developed to deliver STAT3 siRNA to PDGFRβ⁺ Glioblastoma cancer cells. PAMAM Dendrimer was used to deliver EGFR siRNA and miR-150 to suppress STAT5 expression in colon cancer cells and AML cells, respectively. Polypeptide PEGylated-anisamide-LPH nanoparticle was used to transfect lung cancer cells with STAT5B targeting non-apeptide, EV.