MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity <i>via</i> Direct Binding to the STAT3 DNA-Binding Domain

Son, Dong Ju; Zheng, Jun; Jung, Yu Yeon; Hwang, Chul Ju; Lee, Hee Pom; Woo, Ju Rang; Baek, Song Yi; Ham, Young Wan; Kang, Min Ji; Shong, Minho; Kweon, Gi Ryang; Song, Min Jong; Jung, Jae Kyung; Han, Sang‐Bae; Kim, Bo Yeon; Yoon, Do Young; Choi, Bu Young; Hong, Jin Tae

doi:10.7150/thno.18630

Cited by 33 publications

(30 citation statements)

References 30 publications

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“…An LC28 analog, MMPP exhibits the strongest binding affinity to STAT3 and binds selectively to the DBD, especially to T456. MMPP effectively inhibits STAT3 in vitro and in vivo and induces G1-phase cell cycle arrest and apoptosis [ 192 ]. On the basis of the conjugation of a diarylidenyl-piperidone (DAP) backbone to a nitroxide precursor, Kellie identified a novel small-molecule inhibitor, HO-3867, a curcumin analog that directly interacts with the STAT3 DNA-binding domain.…”

Section: Stat3 As a Therapeutic Targetmentioning

confidence: 99%

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Yang

Liu

et al. 2020

Cancers

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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.

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Section: Stat3 As a Therapeutic Targetmentioning

confidence: 99%

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Yang

Liu

et al. 2020

Cancers

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“…Major clinical breakthroughs in late stage lung cancer have been facilitated by the recent advent of patient selection based upon tumor genetic profiles that have promoted a personalized medicine approach for non-small cell lung patients (NSCLC) [4]. Typical treatment for NSCLC is chemotherapy for inhibiting several receptors and intracellular signaling such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), insulin-like growth factor 1 receptor (IGF-1R), RAS proto-oncogene (RAS), mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3) [5][6][7][8]. However, the targeted chemotherapies are their effects only in a small fraction of lung cancer patients who have the corresponding molecular alteration that responds to the appropriate treatment [3,5].…”

Section: Introductionmentioning

confidence: 99%

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

et al. 2020

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Background: Chitinase 3 like 1 protein (Chi3L1) is expressed in several cancers, and a few evidences suggest that the secreted Chi3L1 contributes to tumor development. However, the molecular mechanisms of intracellular Chi3L1 are unknown in the lung tumor development. Methods: In the present study, we generated Chi3L1 knockout mice (Chi3L1 KO(−/−) ) using CRISPR/Cas9 system to investigate the role of Chi3L1 on lung tumorigenesis. Results:We established lung metastasis induced by i.v. injections of B16F10 in Chi3L1 KO(−/−) . The lung tumor nodules were significantly reduced in Chi3L1 KO(−/−) and protein levels of p53, p21, BAX, and cleaved-caspase 3 were significantly increased in Chi3L1 KO(−/−) , while protein levels of cyclin E1, CDK2, and phsphorylation of STAT3 were decreased in Chi3L1 KO(−/−) . Allograft mice inoculated with B16F10 also suppressed tumor growth and increased p53 and its target proteins including p21 and BAX. In addition, knockdown of Chi3L1 in lung cancer cells inhibited lung cancer cell growth and upregulated p53 expression with p21 and BAX, and a decrease in phosphorylation of STAT3. Furthermore, we found that intracellular Chi3L1 physically interacted and colocalized with p53 to inhibit its protein stability and transcriptional activity for target genes related with cell cycle arrest and apoptosis. In lung tumor patient, we clinically found that Chi3L1 expression was upregulated with a decrease in p53 expression, as well as we validated that intracellular Chi3L1 was colocalized, reversely expressed, and physically interacted with p53, which results in suppression of the expression and function of p53 in lung tumor patient.Conclusions: Our studies suggest that intracellular Chi3L1 plays a critical role in the lung tumorigenesis by regulating its novel target protein, p53 in both an in vitro and in vivo system.

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“…In our study, MMPP inhibited STAT3 DNA binding and transcriptional activity, suggesting that MMPP can inhibit neuroinflammation through inactivation of astrocytes via blocking STAT3-mediated p38 and JNK MAPK pathways. Previously, we reported that MMPP has anti-inflammatory effects in inflammatory disease models such as AD, rheumatoid arthritis, and cancer [29,49,50]. We did not detect any side effects of MMPP with the effective dose of MMPP (5 mg/kg) during treatment for 30 days [29].…”

Section: Discussionmentioning

confidence: 65%

“…We have demonstrated that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB) possesses anti-inflammatory properties by inhibiting STAT3 activation in arthritis [26], cancer [27], and AD [28]. The upgraded BHPB analogue, (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) [29], binds strongly to STAT3 through a direct molecular interaction with the hydroxyl residue in the core fragment of STAT3, thereby inhibiting activation of STAT3. Here, we investigated whether MMPP could prevent MPTP-induced neurodegenerative damage by inhibiting MAPK/STAT3 activation.…”

Section: Introductionmentioning

confidence: 99%

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

Choi

Yun

Hwang

et al. 2019

IJMS

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Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.

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MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain

Cited by 33 publications

References 30 publications

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

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