[Retracted] Brusatol Inhibits Proliferation and Metastasis of Colorectal Cancer by Targeting and Reversing the RhoA/ROCK1 Pathway

Lu, Ruijin; Zhao, Guozhi; Jiang, Rong; He, Shuang; Xu, Hang; He, Jiaming; Sun, Yue; Wu, Mengna; Ran, Jianhua; Chen, Dilong; Li, Jing

doi:10.1155/2022/7132159

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…Brusatol (Bru; Figure 1 ) is a quassinoid plant extract isolated from the Brucea species plant, capable of inducing various biological effects, including antimalarial, anti-inflammatory, and antineoplastic. Its potential as an antineoplastic drug was reported in several solid tumors, such as pancreatic cancer (PC), non-small cell lung cancer (NSCLC), renal cell cancer (RCC), among others [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ], as well as in hematological malignancies and particularly acute myeloid leukemia (AML) [ 18 ]. Previous investigations demonstrated that brusatol could act as a global protein synthesis inhibitor [ 19 ], while most studies reported it as an inhibitor of NRF2 signaling by reducing its protein levels through post-transcriptional mechanisms stimulating its ubiquitination and subsequent proteolysis [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

et al. 2022

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Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid plant extract extensively studied due to its antineoplastic effect through global protein synthesis and nuclear factor erythroid 2-related factor-2 (NRF2) signaling inhibition. NRF2 is the main regulator of cellular antioxidant response and reactive oxygen species (ROS), which plays an important role in oxidative stress regulation. This study aimed to evaluate the effect of brusatol in in vitro models of ALL. KOPN-8 (B-ALL), CEM (T-ALL), and MOLT-4 (T-ALL) cell lines were incubated with increasing concentrations of brusatol, and the metabolic activity was evaluated using the resazurin assay. Flow cytometry was used to evaluate cell death, cell cycle, mitochondrial membrane potential (Δψmit), and to measure ROS and reduced glutathione (GSH) levels. Our results show that brusatol promoted a decrease in metabolic activity in ALL cell lines in a time-, dose-, and cell-line-dependent manner. Brusatol induced a cytostatic effect by cell cycle arrest in G0/G1 in all cell lines; however, cell death mediated by apoptosis was only observed in T-ALL cells. Brusatol leads to an oxidative stress imbalance by the increase in ROS levels, namely, superoxide anion. Redox imbalance and cellular apoptosis induced by brusatol are highly modulated by mitochondria disruption as a decrease in mitochondrial membrane potential is detected. These data suggest that brusatol might represent a new therapeutic approach for acute lymphoblastic leukemia, particularly for ALL T-cell lineage.

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Section: Introductionmentioning

confidence: 99%

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

et al. 2022

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“…Thus, they concluded that Ggps1 deletion disrupts the RhoA/Rock2 pathway, causing uterine contraction and parturition problems. Interestingly, Rho has been found to regulate MMP expression at various cell types [42–44], raising the possibility that they are also co-involved in governing parturition process.…”

Section: Discussionmentioning

confidence: 99%

MMP2 loss leads to defective parturition and severe dystocia in mice

Kalev-Altman

Levy

Shpigel

et al. 2022

Preprint

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Parturition is the final step of mammalian reproduction and an essential process for the species survival. During pregnancy, the uterus is maintained quiescence which is important for fetal growth and development. However, at term, fundamental changes in myometrial contractility are initiated for efficient expulsion of the fetus. These changes involve tissue remodeling that requires changes in the extracellular matrix (ECM). The gelatinases subgroup of matrix metalloproteinases (MMPs), has only two members: MMP2 and MMP9, which are both known to participate in uterine ECM remodeling throughout the estrus cycle as well as during pregnancy, parturition and postpartum involution. Yet, no knowledge exists regarding their loss-of-function impact on the uterus. Here we investigated the effect of MMP2 and/or MMP9 genetic loss on parturition process. Single and double knockout (dKO) mice for MMP2 and/or MMP9 were used. We found high percentages of dystocia in mmp2-/-, mmp2-/-mmp9+/- and dKO females, but not in mmp9-/- females. Histological analysis of nulliparous uterine tissue of WT, mmp2-/-, mmp9-/- and dKO, at 8 weeks, 4 months and 8-9.5 months, revealed that the uterine tissue of mmp2-/- presents alterations in tissue size and structure, mainly when reaching to 8-9.5 months of age, including enlarged total tissue, myometrium, endometrium and luminal cavity. Additionally, Masson Trichrome staining suggested a mechanism of extensive fibrosis in mmp2-/- myometrium, which may lead to dystocia. Altogether, our research highlights a novel cause for dystocia pathology mediated by loss of MMP2 activity in uterine tissue during mammalian parturition.

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“…Western blot assay was carried out in BBR and functional experiments in MCF7 and MDA-MB-231 cells. The detailed procedures have been described in our previous study [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

“…mRNA and cDNA were carried out as described previously [ 50 ]. The 2 −ΔΔCt approach was utilized to assess relative expression levels, with GAPDH as an internal control.…”

Section: Methodsmentioning

confidence: 99%

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

Wei

Luan

et al. 2022

Pharmaceuticals

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Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy.

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[Retracted] Brusatol Inhibits Proliferation and Metastasis of Colorectal Cancer by Targeting and Reversing the RhoA/ROCK1 Pathway

Cited by 14 publications

References 42 publications

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

MMP2 loss leads to defective parturition and severe dystocia in mice

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial–Mesenchymal Transition

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