EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

Chakraborty, Sukanya; Bhat, Aaqib M.; Mushtaq, Insha; Luan, Haitao; Kalluchi, Achyuth; Mirza, Sameer; Storck, Matthew D.; Chaturvedi, Nagendra K.; López-Guerrero, José Antonio; Llombart‐Bosch, Antonio; Machado, Isidro; Scotlandi, Katia; Meza, Jane L.; Ghosal, Gargi; Coulter, Donald W.; Rowley, M. Jordan; Mohapatra, Bhopal; Band, Vimla

doi:10.1038/s42003-023-05125-1

“…Expression analysis of ES-associated signature genes and molecules involved in disease-associated signaling pathways has previously been conducted [24][25][26]. To assess the potential impact of inhibiting CAII-mediated pathways on ES tumor proliferation and migration, we employed several low-to sub-nanomolar CAII inhibitors.…”

Section: Inhibition Of Caii Decreases Es Tumor Cell Proliferationmentioning

confidence: 99%

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells

Fayzullina,

Yakushov,

Kantserova

et al. 2023

Cancers

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Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.

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“…Mechanistically, EHD1 promotes the trafficking of insulin-like growth factor 1 receptor and other receptor tyrosine kinases to the cell surface, therefore promoting tumorigenesis and metastasis [26]. Mutations in EHD1 are associated with tubular proteinuria and deafness in human [27].…”

Section: Introductionmentioning

confidence: 99%

Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4

Mohd,

Oder,

Specker

et al. 2024

Preprint

0

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Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain-containing proteins (EHDs) comprise a family of eukaryotic dynamin-related ATPases that participate in various endocytic membrane trafficking pathways. Dysregulation of EHDs function has been implicated in various diseases, including cancer. The lack of small molecule inhibitors which acutely target individual EHD members has hampered progress in dissecting their detailed cellular membrane trafficking pathways and their function during disease. Here, we established a Malachite green-based assay compatible with high throughput screening to monitor the liposome-stimulated ATPase of EHD4. In this way, we identified a drug-like molecule that inhibited EHD4’s liposome-stimulated ATPase activity. Structure activity relationship (SAR) studies indicated sites of preferred substitutions for more potent inhibitor synthesis. Moreover, the assay optimization in this work can be applied to other dynamin family members showing a weak and liposome-dependent nucleotide hydrolysis activity.

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“…For example, EHD1 is overexpressed in several cancers, which appears to mediate chemotherapy resistance, epithelial-mesenchymal transition and stem cell behavior [ 23 – 25 ]. Mechanistically, EHD1 promotes the trafficking of insulin-like growth factor 1 receptor and other receptor tyrosine kinases to the cell surface, therefore promoting tumorigenesis and metastasis [ 26 ]. Mutations in EHD1 are associated with tubular proteinuria and deafness in human [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4

Mohd,

Oder,

Specker

et al. 2024

PLoS ONE

0

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Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain-containing proteins (EHDs) comprise a family of eukaryotic dynamin-related ATPases that participate in various endocytic membrane trafficking pathways. Dysregulation of EHDs function has been implicated in various diseases, including cancer. The lack of small molecule inhibitors which acutely target individual EHD members has hampered progress in dissecting their detailed cellular membrane trafficking pathways and their function during disease. Here, we established a Malachite green-based assay compatible with high throughput screening to monitor the liposome-stimulated ATPase of EHD4. In this way, we identified a drug-like molecule that inhibited EHD4’s liposome-stimulated ATPase activity. Structure activity relationship (SAR) studies indicated sites of preferred substitutions for more potent inhibitor synthesis. Moreover, the assay optimization in this work can be applied to other dynamin family members showing a weak and liposome-dependent nucleotide hydrolysis activity.

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EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

Cited by 4 publications

References 84 publications

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells

Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4

Identification of drug-like molecules targeting the ATPase activity of dynamin-like EHD4

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