Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells

Park, So Yeon; Kim, Min Jin; Park, Sang-A; Kim, Jung-Shin; Min, Kyung-Nan; Kim, Dae‐Kee; Lim, Woosung; Nam, Jeong‐Seok; Sheen, Yhun Yhong

doi:10.18632/oncotarget.6063

Cited by 66 publications

(79 citation statements)

References 59 publications

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“…Paclitaxel caused non-significant increase in CSCs percentage in both cell lines as compared with the control. Our finding of increased CSCs percentage after paclitaxel alone treatment corresponds to finding by others 26. Combined treatment with paclitaxel and compound 1 abolished the effect of compound 1 in reducing CSCs with paclitaxel increasing CSCs more efficiently than the decrease induced by compound 1 .…”

Section: Resultssupporting

confidence: 91%

Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3-<em>b</em>]pyridine anticancer compound

Mastelić¹,

Čulić²,

Mužinić³

et al. 2017

DDDT

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Tumor progression may be driven by a small subpopulation of cancer stem cells (CSCs characterized by CD44+/CD24− phenotype). We investigated the influence of a newly developed thienopyridine anticancer compound (3-amino-5-oxo-N-naphthyl-5,6,7, 8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1) on the growth, survival and glycophenotype (CD15s and GM3 containing neuraminic acid substituted with acetyl residue, NeuAc) of breast and prostate cancer stem/progenitor-like cell population. MDA-MB-231 and Du-145 cells were incubated with compound 1 alone or in combination with paclitaxel. The cellular metabolic activity was determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The type of cell death induced by 48-h treatment was assessed using a combination of Annexin-V-FITC and propidium iodide staining. Flow cytometric analysis was performed to detect the percentage of CD44+/CD24− cells, and GM3 and CD15s positive CSCs, as well as the expression of GM3 and CD15s per one CSC, in both cell lines. Compound 1 produces a dose- and time-dependent cytotoxicity, mediated mainly by apoptosis in breast cancer cells, and slightly (2.3%) but statistically significant lowering breast CSC subpopulation. GM3 expression per one breast CSC was increased, and the percentage of prostate GM3+ CSC subpopulation was decreased in cells treated with compound 1 compared with non-treated cells. The percentage of CD15s+ CSCs was lower in both cell lines after treatment with compound 1. Considering that triple-negative breast cancers are characterized by an increased percentage of breast CSCs and knowing their association with an increased risk of metastasis and mortality, compound 1 is a potentially effective drug for triple-negative breast cancer treatment.

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Section: Resultssupporting

confidence: 91%

Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3-<em>b</em>]pyridine anticancer compound

Mastelić¹,

Čulić²,

Mužinić³

et al. 2017

DDDT

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“…For example, in breast cancer the EMT state has been associated with cancer stem cell properties including the expression of stem cell-associated CD44+/CD24-/low antigenic profile, self-renewal capabilities and resistance to conventional therapies [34–36]. Our previous study has shown that mesenchymal-derived osteosarcoma did not express epithelial markers, however, osteosarcoma stem cells express more mesenchymal markers and showed higher motility [13].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

Fan

Fang

et al. 2016

Oncotarget

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Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance.

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“…HIF1α increases expression levels of NOXs, which results in ROS generation [59,60], regulating the transcriptional activity of HIF1α and driving the EMT [46,61]. In addition, ROS generation induces Snail expression, subsequently leading to the EMT [62,63] This study also showed that HIF1α increased ROS generation via NOX4 and demonstrated that ROS induced the EMT by inducing Snail expression in the livers of BDL rats and LX-2 cells (Fig. 5 and 6).…”

Section: Discussionmentioning

confidence: 99%

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

Kim

Park

Kim

et al. 2016

Cell Physiol Biochem

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Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.

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Combinatorial TGF-β attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells

Cited by 66 publications

References 59 publications

Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3-<em>b</em>]pyridine anticancer compound

Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3-<em>b</em>]pyridine anticancer compound

Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

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