STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Yang, Ping-Lian; Liu, Lu-Xin; Li, En‐Min; Xu, Li‐Yan

doi:10.3390/cancers12092459

Cited by 22 publications

(23 citation statements)

References 227 publications

(279 reference statements)

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“…There are now several Phase I clinical trials ongoing for hematological malignancies (including acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndrome, myeloma multiple) [ 79 ], which are evaluating one inhibitor from Servier and Vernalis (R&D) Ltd. (S63415/MIK655), two from Amgen (AMG176 and AMG397) and one from AstraZeneca (AZD5991). Small-molecule STAT3 inhibitors of different STAT3 domains have been identified via the screening of chemical libraries and computational docking [ 11 , 12 , 80 ]. STAT3 inhibitors that target the SH2 domain of STAT3 (OPB-31121 and OPB-51602 from Otsuka Pharmaceuticals Co. Ltd.) have completed Phase I/II studies [ 12 ].…”

Section: Resultsmentioning

confidence: 99%

“…Small-molecule STAT3 inhibitors of different STAT3 domains have been identified via the screening of chemical libraries and computational docking [ 11 , 12 , 80 ]. STAT3 inhibitors that target the SH2 domain of STAT3 (OPB-31121 and OPB-51602 from Otsuka Pharmaceuticals Co. Ltd.) have completed Phase I/II studies [ 12 ]. All these compounds are expected to progress in further clinical trials, and pave a new avenue for cancer therapy not only in the field of CLL but also in the general treatment of cancer.…”

Section: Resultsmentioning

confidence: 99%

“…Both type I and II IFNs signal through activation of receptor-associated Janus kinases (JAKs)/signal transducers and activators of transcription (STAT) pathways [ 4 , 5 , 6 , 7 ]. Aberrant STAT3 expression and activation (through phosphorylation) is observed in various solid and hematological tumors, and is associated with tumor growth and progression [ 10 , 11 , 12 , 13 ]. Type I and II IFNs promote specific phosphorylation of STAT3 at tyrosine 705 (p Y705 ), allowing its dimerization, nuclear translocation, and transcriptional activation of target genes involved in cell proliferation, cell survival and metastasis [ 6 , 11 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Type I and II IFNs promote specific phosphorylation of STAT3 at tyrosine 705 (p Y705 ), allowing its dimerization, nuclear translocation, and transcriptional activation of target genes involved in cell proliferation, cell survival and metastasis [ 6 , 11 , 14 ]. Conversely, downregulation of STAT3 signaling inhibits tumor growth and induction of cell death in preclinical models [ 11 , 12 ]. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and thereby impairs therapeutic efficacy [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, downregulation of STAT3 signaling inhibits tumor growth and induction of cell death in preclinical models [ 11 , 12 ]. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and thereby impairs therapeutic efficacy [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

et al. 2021

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Besides their antiviral and immunomodulatory functions, type I (αβ) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

et al. 2021

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Apoptotic activity of genipin in human oral squamous cell carcinoma in vitro by regulating STAT3 signaling

Park,

Jin,

Lee

et al. 2023

Cell Biochemistry & Function

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Genipin, a natural compound derived from the fruit of Gardenia jasminoides Ellis, was reported to have activity against various cancer types. In this study, we determined the underlying mechanism for genipin‐induced cell death in human oral squamous cell carcinoma (OSCC). The growth‐inhibitory effects of genipin in human OSCC cells was examined by the Cell Counting Kit‐8 and soft agar assays. The effects of genipin on apoptosis were assessed by nuclear morphological changes by 4′,6‐diamidino‐2‐phenylindole staining, measurement of the sub‐G1 population, and Annexin V‐fluorescein isothiocyanate/propidium iodide double staining. The underlying mechanism of genipin activity was analyzed by western blot analysis, subcellular fractionation of the nucleus and cytoplasm, immunocytochemistry, and quantitative real‐time polymerase chain reaction. Genipin inhibited the growth of OSCC cells and induced apoptosis, which was mediated by a caspase‐dependent pathway. Genipin reduced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and its nuclear localization. Furthermore, inhibition of p‐STAT3Tyr705 levels following genipin treatment was required for the reduction of survivin and myeloid cell leukemia‐1 (Mcl‐1) expression, leading to apoptotic cell death. The genipin‐mediated reduction in survivin and Mcl‐1 expression was caused by transcriptional and/or posttranslational regulatory mechanisms. The results provide insight into the regulatory mechanism by which genipin induces apoptotic cell death through the abrogation of nuclear STAT3 phosphorylation and suggest that genipin may represent a potential therapeutic option for the treatment of human OSCC.

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TXNL4B regulates radioresistance by controlling the PRP3‐mediated alternative splicing of FANCI

Zhao

Jing

Xiao

et al. 2023

MedComm

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Ionizing radiation (IR) has been extensively used for cancer therapy, but the radioresistance hinders and undermines the radiotherapy efficacy in clinics greatly. Here, we reported that the spliceosomal protein thioredoxin‐like 4B (TXNL4B) is highly expressed in lung tissues from lung cancer patients with radiotherapy. Lung cancer cells with TXNL4B knockdown illustrate increased sensitivity to IR. Mechanistically, TXNL4B interacts with RNA processing factor 3 (PRP3) and co‐localizes in the nucleus post‐IR. Nuclear localization of PRP3 promotes the alternative splicing of the Fanconi anemia group I protein (FANCI) transcript variants, FANCI‐12 and FANCI‐13. PRP3 regulates alternative splicing of FANCI toward the two variants, FANCI‐12 and FANCI‐13. Radioresistance was greatly enhanced through the combination of PRP31 and PRP8, the critical components of core spliceosome promoted by PRP3. Notably, the inhibition of PRP3 to suppress the production of FANCI‐12 would deprive PRP31 and PRP8 of such interaction. As a result, cell cycle G2/M arrest was induced, DNA damage repair was delayed, and radiosensitivity was improved. Collectively, our study highlights potential novel underlying mechanisms of the involvement of TXNL4B and alternative splicing in radioresistance. The results would benefit potential cancer radiotherapy.

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STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Cited by 22 publications

References 227 publications

Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

Apoptotic activity of genipin in human oral squamous cell carcinoma in vitro by regulating STAT3 signaling

TXNL4B regulates radioresistance by controlling the PRP3‐mediated alternative splicing of FANCI

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