Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer-Drug Carriers Matter

Abstract

High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.

Keywords: STAT3; cancer therapy; drug delivery systems; nanoparticles; oligonucleotide-based therapeutics.

Figure 1

Activation of STAT3 in cancer. The STAT3 pathway is activated by a variety of receptors, such as cytokine receptors, receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and toll-like receptors (TLRs). As a result of receptor stimulation, STAT3 is activated through tyrosine phosphorylation. Moreover, STAT3 may be activated by non-receptor tyrosine kinases, including c-Src. Phosphorylated STAT3 dimers translocate to the nucleus, binding to DNA and promoting the expression of specific genes involved in cancer progression. The figure was partly created using the Servier Medical Art Commons Attribution 3.0 Unported Licence.

Figure 2

The role of STAT3 in cancer development. STAT3 signaling is involved in many cancer-related processes. Activated STAT3 upregulates the expression of genes related to cell proliferation, anti-apoptosis, drug resistance, and stem-like phenotypes, resulting in the uncontrolled growth of cells, angiogenesis, immune evasion, migration, and invasion. Legend: green arrow—increase, red arrow—decrease. The figure was partly created using the Servier Medical Art Commons Attribution 3.0 Unported Licence.

Figure 3

STAT3-targeting strategies with oligonucleotide-based therapeutics. Oligonucleotide therapeutics used in STAT3-inhibiting therapies are oligodeoxynucleotide decoys (ODN-decoys), antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and short hairpin RNA (shRNA). ODN-decoys are double-stranded oligodeoxynucleotides that mimic the binding sequence of STAT3. ASOs, the single-stranded deoxyribonucleic acids, selectively bind to a transcription product, leading to their degradation by the RNase H pathway. RNA interference (RNAi) molecules, siRNA and shRNA, associate with the RNA-induced silencing complex (RISC) and anneal to the target mRNA and lead to its degradation and thus gene expression silencing. The figure was partly created using the Servier Medical Art Commons Attribution 3.0 Unported Licence.