Abstract
Simple SummarySTAT3, an oncogene, contributes to insensitivity of chemotherapy and radiotherapy in tumor, reduces the clinical efficacy. Meanwhile, STAT3β, a STAT3 splicing isoform, is related to the inhibition of tumor growth and chemosensitivity. STAT3 may become a potential target to overcome the chemo(radio)resistance, which benefit for developing novel drugs targeting STAT3 or alternative splicing regulators.Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3β is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3β as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3β on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.
Highlights
Chemoradiotherapy is the main treatment for various solid malignancies through the induction of tumor DNA damage, and it can be used alone or in combination with surgery
In the context of a high expression level of AKT, protein kinase B; CSCs, cancer stem cells; epidermal growth factor protein-1 (EGFR), epidermal growth factor receptor; epithelial–mesenchymal transition (EMT), STAT3β, receptor tyrosine kinases (RTKs) inhibitors that activate Signal transducer and activator of transcription 3 (STAT3) via a feedback loop may be of benefit for cell apoptosis
STAT3β expression is correlated with overall survival and recurrence-free survival in esophageal squamous cell carcinoma (ESCC) patients with or without chemoradiotherapy and sensitizes tumor xenografts to chemotherapy mainly by blocking the transcriptional activity of STAT3α [96]
Summary
Chemoradiotherapy is the main treatment for various solid malignancies through the induction of tumor DNA damage, and it can be used alone or in combination with surgery. Signal transducer and activator of transcription (STAT) proteins are a family of cytoplasmic transcription factors and were discovered by James E. STAT3β is an alternatively spliced variant, in which the 55 C-terminal amino acid residues of STAT3α, including serine 727, are replaced by seven amino acid residues (FIDAVWK). 12, 2459 regulate the proportion of STAT3α/STAT3β (Figure 1) [20]. STAT3β is generally considered a dominant-negative regulator of STAT3α. It still acts as a significant transcriptional transduction [8].own. STAT3 deficiency causeswith earlyother embryonic proteins, and consists of an amino-terminal domain (NTD). DNA lethality, STAT3β itself can rescue the embryonic lethality [31,32,33]. Structure andand thethe alternative splicing pattern of STAT3
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