Overview of the STAT‑3 signaling pathway in cancer and the development of specific inhibitors (Review)

Abstract

Signal transducer and activator of transcription (STAT) proteins represent novel therapeutic targets for the treatment of cancer. In particular, STAT-3 serves critical roles in several cellular processes, including the cell cycle, cell proliferation, cellular apoptosis and tumorigenesis. Persistent activation of STAT-3 has been reported in a variety of cancer types, and a poor prognosis of cancer may be associated with the phosphorylation level of STAT-3. Furthermore, elevated STAT-3 activity has been demonstrated in a variety of mammalian cancers, both in vitro and in vivo. This indicates that STAT-3 serves an important role in the progression of numerous cancer types. A significant obstacle in developing STAT-3 inhibitors is the demonstration of the antitumor efficacy in in vivo systems and the lack of animal models for human tumors. Therefore, it is crucial to determine whether available STAT-3 inhibitors are suitable for clinical trials. Moreover, further preclinical studies are necessary to focus on the impact of STAT-3 inhibitors on tumor cells. When considering STAT-3 hyper-activation in human cancer, selective targeting to these proteins holds promise for significant advancement in cancer treatment. In the present study, advances in our knowledge of the structure of STAT-3 protein and its regulatory mechanisms are summarized. Moreover, the STAT-3 signaling pathway and its critical role in malignancy are discussed, in addition to the development of STAT-3 inhibitors in various cancer types. Contents 1. Introduction 2. STAT-3 structure 3. STAT-3 signal transduction cascade 4. Target genes regulated by STAT-3 5. Advances in antitumor therapeutics targeting STAT-3 6. Conclusions

An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target

“…Constitutive overactivation of STAT3 is known to be implicated in the pathogenesis of tumor development and progression [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Therefore, the inhibition of abnormally elevated STAT3 activity or expression represents a rational therapeutic modality for malignancies, including breast cancer [ 23 , 25 , 26 , 29 , 30 , 31 , 32 , 33 , 46 ]. The blockage of aberrant STAT3 activation by genetic or pharmacological approaches has been achieved by the use of small molecular weight inhibitors, protein inhibitors, dominant-negative STAT3 mutants, antisense RNA, and interference oligonucleotides (RNAi).…”

“…It is well known that STAT3 is involved in the transcriptional regulation of genes encoding apoptosis inhibitors (e.g., Bcl-xL) and cell-cycle regulators (e.g., Cyclin D1) [ 24 , 25 , 26 ]. However, the SH48-induced suppression of STAT3 did not lead to apoptosis but rather induced autophagy in MCF10A- ras cells.…”

“…Among these, STAT3 is a transcription factor that is involved in tumor development and progression as well as inflammation [ 22 , 23 , 24 , 25 ]. STAT3 is constitutively activated in several cancer cells [ 23 , 24 , 25 , 26 ]. The aberrantly activated STAT3 is believed to contribute to malignant transformation at several levels, including uncontrolled proliferation through activation of several cell-cycle regulators, (e.g., Cyclin D1 and c-Myc) as well as the evasion of apoptosis by inducing the expression of anti-apoptotic proteins (e.g., Bcl-xL, Bcl-2, Mcl-1, and Survivin) [ 24 , 25 , 26 ].…”

“…STAT3 is constitutively activated in several cancer cells [ 23 , 24 , 25 , 26 ]. The aberrantly activated STAT3 is believed to contribute to malignant transformation at several levels, including uncontrolled proliferation through activation of several cell-cycle regulators, (e.g., Cyclin D1 and c-Myc) as well as the evasion of apoptosis by inducing the expression of anti-apoptotic proteins (e.g., Bcl-xL, Bcl-2, Mcl-1, and Survivin) [ 24 , 25 , 26 ]. STAT3 also mediates the expression of proteins involved in other hallmarks of cancer, such as invasion/metastasis [ 27 ] and angiogenesis [ 28 ].…”

“…STAT3 also mediates the expression of proteins involved in other hallmarks of cancer, such as invasion/metastasis [ 27 ] and angiogenesis [ 28 ]. Therefore, STAT3 is considered to be an important target for the development of cancer therapeutic agents [ 23 , 25 , 26 , 29 , 30 , 31 , 32 , 33 ]. The suppression of a STAT3 signal pathway by deguelin has been observed in adult T cells transformed by human T-cell leukemia virus [ 34 ].…”