High content screening identifies monensin as an EMT-selective cytotoxic compound

Vanneste, Marion; Huang, Qin; Li, Mengshi; Moose, Devon L.; Zhao, Lei; Stamnes, Mark; Schultz, Michael K.; Wu, Meng; Henry, Michael D.

doi:10.1038/s41598-018-38019-y

Cited by 31 publications

(27 citation statements)

References 54 publications

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“…Salinomycin, an antibacterial and coccidiostat ionophore, has been shown to efficiently suppress BCSC survival ( Gupta et al, 2009 ; Zhou et al, 2013 ). Strikingly, TAZ DEP cells are 100-fold more sensitive to Salinomycin treatment than TAZ IND cells ( Figure 3C ), which is consistent with monovalent cation ionophores’ potent and cytostatic effects against EMT-like cells and therapy-resistant cancer cells ( Vanneste et al, 2019 ).…”

Section: Resultssupporting

confidence: 75%

Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

Shen

Chen

Wan

et al. 2021

Front. Cell Dev. Biol.

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Breast cancer stem cells (BCSCs) represent a subpopulation of tumor cells that can self-renew and generate tumor heterogeneity. Targeting BCSCs may ameliorate therapy resistance, tumor growth, and metastatic progression. However, the origin and molecular mechanisms underlying their cellular properties are poorly understood. The transcriptional coactivator with PDZ-binding motif (TAZ) promotes mammary stem/progenitor cell (MaSC) expansion and maintenance but also confers stem-like traits to differentiated tumor cells. Here, we describe the rapid generation of experimentally induced BCSCs by TAZ-mediated reprogramming of human mammary epithelial cells, hence allowing for the direct analysis of BCSC phenotypes. Specifically, we establish genetically well-defined TAZ-dependent (TAZDEP) and -independent (TAZIND) cell lines with cancer stem cell (CSC) traits, such as self-renewal, variable resistance to chemotherapeutic agents, and tumor seeding potential. TAZDEP cells were associated with the epithelial to mesenchymal transition, embryonic, and MaSC signature genes. In contrast, TAZIND cells were characterized by a neuroendocrine transdifferentiation transcriptional program associated with Polycomb repressive complex 2 (PRC2). Mechanistically, we identify Cyclin D1 (CCND1) as a critical downstream effector for TAZ-driven tumorigenesis. Overall, our results reveal a critical TAZ-CCND1-CDK4/CDK6 signaling axis, suggesting novel therapeutic approaches to eliminate both BCSCs and therapy-resistant cancer cells.

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Section: Resultssupporting

confidence: 75%

Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

Shen

Chen

Wan

et al. 2021

Front. Cell Dev. Biol.

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“…prostate cancer cells undergoing epithelial-mesenchymal transition [46], whereas Niclosamide can direct pericellular lysosomes of DU145 prostate cancer cells to perinuclear positions, indicating its effect on lysosome-mediated invasion [47]. The commonly used anticancer drugs etoposide and teniposide are derivatives of Podophyllotoxin.…”

Section: Discussionmentioning

confidence: 99%

Identification of lysosome‐targeting drugs with anti‐inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers

et al. 2021

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Purpose Most HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers. Methods We used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug’s ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation. Results We identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither. Conclusions Our results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.

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“…Monensin, is an antibiotic with ionophore qualities that exchanges Na+, K+ and protons across membranes affecting physiological microenvironment of the cell mainly affecting the acidification of membrane compartments (Pressman & Fahim, 1982). This drug tends to bind to cholesterol rich structures such as the ones present in the Golgi apparatus (Vanneste et al, 2019), also has been described…”

Section: Discussionmentioning

confidence: 99%

Golgi apparatus components in Entamoeba histolytica and Entamoeba dispar after monensin treatment

Talamás‐Lara

Acosta-Virgen

Chávez‐Munguía

et al. 2021

Microscopy Res & Technique

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Highly dynamic ribosomes, glycogen granules, thinly fibrillar material, and multiple membrane-bound vesicles are embedded in the matrix-rich cytoplasm of Entamoeba spp. trophozoites. The absence of a Golgi apparatus in these amoebae has been commonly accepted. Here we challenge this observation by incubating Entamoeba histolytica and Entamoeba dispar with monensin, an ionophore that produces swelling of the Golgi apparatus. We observe changes in the trophozoites through standard transmission electron microscopy, cryofixation and cryosubstitution, and analyze the label and expression of known resident proteins of the cis-GM130 and trans-TGN38 Golgi network through confocal microscopy and Western blot assays. Cryosubstitution and standard methods using the treatment, preserved membranous lamellae resembling Golgi components. GM130 and TGN38 Golgi antigens were found by immunoelectron, immunoblot, and co-localization by confocal microscopy using the reagent NBD C6-ceramide. Our results indicate that previously undetected Golgi apparatus components are present in the cytoplasm of E. histolytica and E. dispar.

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High content screening identifies monensin as an EMT-selective cytotoxic compound

Cited by 31 publications

References 54 publications

Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

Identification of lysosome‐targeting drugs with anti‐inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers

Golgi apparatus components in Entamoeba histolytica and Entamoeba dispar after monensin treatment

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