Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo

Xie, Xiaodong; Liu, Kangdong; Liu, Feifei; Chen, Hanyong; Wang, Xiangyu; Zu, Xueyin; Wang, Ting; Wu, Qiong; Zheng, Yan; Bode, Ann M.; Dong, Zigang; Kim, Dong Joon

doi:10.1016/j.canlet.2018.10.016

Cited by 39 publications

(31 citation statements)

References 48 publications

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“…Esophageal cancer is one of the most common malignant tumors, the mortality of which ranks 6th around the world with poor overall survival 1 . Esophageal cancer has two major histologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma 2 , and ESCC is the main histologic subtype with ~90% of cases in Asia-Pacific region including China. Failure of chemotherapy and radiotherapy leads to tumor recurrence and poor prognosis mainly due to limited efficiency and side effects, for example, conventional chemotherapeutics target both cancer cells and normal cells resulting in toxic effects on the body 3 , 4 .…”

Section: Introductionmentioning

confidence: 99%

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

et al. 2020

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Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.

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Section: Introductionmentioning

confidence: 99%

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

et al. 2020

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“…The loss of p38-activation may promote tumor growth in cancers with a decreased level of MKK3 [57,75], suggesting its tumor-suppressive function. On the other hand, the oncogenic role for MKK3 has been reported in multiple tumor types, including melanoma, colorectal, liver, esophageal, cervical, and breast cancers [51,52,[76][77][78][79][80]. Analysis of genomics data shows that MKK3 is either up-or downregulated in different cancer types and different groups of cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…The loss of p38-activation may promote tumor growth in cancers with a decreased level of MKK3 [ 57 , 75 ], suggesting its tumor-suppressive function. On the other hand, the oncogenic role for MKK3 has been reported in multiple tumor types, including melanoma, colorectal, liver, esophageal, cervical, and breast cancers [ 51 , 52 , 76 – 80 ].…”

Section: Discussionmentioning

confidence: 99%

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients

et al. 2020

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Background: African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort. Methods: The systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fullyconvolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images. Results: We found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC. Conclusions: The poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein-protein interaction as a new promising target to reduce racial disparity in breast cancer survival.

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“…Esophageal cancer (EC) ranks seventh and sixth in global incidence and mortality, respectively, for malignant tumors (Bray et al, 2018) with esophageal squamous cell carcinoma (ESCC) being the main histological form (He et al, 2017;Song et al, 2018;Xie et al, 2019). According to recent epidemiological investigations, the recurrence rates after middle and late stage treatment of patients with ESCC are high, and the five-year survival rate is less than 20%, (Lin et al, 2018;Liu et al, 2019;Xie et al, 2019). Therefore, it is of particularly urgency to identify compounds that may prevent ESCC recurrence and to elucidate their underlying molecular mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Proteomics Reveal the Inhibitory Mechanism of Levodopa Against Esophageal Squamous Cell Carcinoma

et al. 2020

Front. Pharmacol.

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High recurrence rates and poor survival of patients with esophageal squamous cell carcinoma (ESCC) after treatment make ongoing research on chemoprevention drugs for ESCC particularly important. In this study, we screened a large number of FDA-approved drugs and found levodopa, a drug used to treat Parkinson's disease, had an inhibitory effect on the growth of ESCC cells. To elucidate the molecular mechanisms involved, we applied quantitative proteomics to investigate the anti-tumor activity of levodopa on ESCC. The results suggest that levodopa could down-regulate oxidative phosphorylation, non-alcoholic fatty liver disease, and Parkinson's disease pathways. Major mitochondrial respiratory compounds were involved in the pathways, including succinate dehydrogenase subunit D, NADH-ubiquinone oxidoreductase Fe-S protein 4, and mitochondrial cytochrome c oxidase subunit 3. Down-regulation of these proteins was associated with mitochondrial dysfunction. Western blotting and immunofluorescence results confirmed the proteomics findings. Cell viability assays indicated mitochondrial activity was suppressed after levodopa treatment. Reduced mitochondrial membrane potential was detected using JC-1 staining and TMRE assays. Transmission electron microscopy revealed changes in the morphology of mitochondria. Taken together, these results indicate that levodopa inhibited the growth of ESCC through restraining mitochondria function.

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Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo

Cited by 39 publications

References 48 publications

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients

Proteomics Reveal the Inhibitory Mechanism of Levodopa Against Esophageal Squamous Cell Carcinoma

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