NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells

Silva, Jean Carlos Lipreri da; Carvalho, Maria Fernanda Lopes; Miranda, Lívia Bassani Lins de; Almeida, Bruna Oliveira de; Lima, Keli; Machado-Neto, João Agostinho

doi:10.1007/s10637-022-01249-z

Cited by 6 publications

(7 citation statements)

References 36 publications

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“…We found that 27% of all HCC samples had a PTEN deletion (Figure 1B). The HCC samples with a PTEN deletion showed lower levels of mRNA expression than those that had diploid PTEN 45 . These data indicate that the reduction in PTEN copy number is likely to be one of the main mechanisms that contributed to the downregulation of PTEN in HCC patients.…”

Section: Resultsmentioning

confidence: 75%

“…Ezrin is a critical structural protein involved in stabilizing membrane receptor complexes 42–44 . Ezrin is highly expressed and reflects an unfavorable prognosis in a number of tumors 45–47 . Our research has shown that NSC305787 inhibits the phosphorylation of ezrin‐T567, resulting in a marked reduction in cell growth (Figure 5F–K).…”

Section: Discussionmentioning

confidence: 78%

“…[42][43][44] Ezrin is highly expressed and reflects an unfavorable prognosis in a number of tumors. [45][46][47] Our research has shown that NSC305787 inhibits the phosphorylation of ezrin-T567, resulting in a marked reduction in cell growth (Figure 5F-K). However, we noted a failure of the ezrin inhibitor to inhibit subcutaneous tumors in mice (data not shown).…”

Section: Discussionmentioning

confidence: 85%

“…The HCC samples with a PTEN deletion showed lower levels of mRNA expression than those that had diploid PTEN. 45 These data indicate that the reduction in PTEN copy number is likely to be one of the main mechanisms that contributed to the downregulation of PTEN in HCC patients. Although the mutation rate of the KRAS gene in liver cancer is only 1.4% (Figure 1A), the frequency of KRAS with DNA copy number gain or amplification (which correlates with increased mRNA expression) in CNV was 11% (Figure 1B).…”

Section: Construction Of Four Primary Mouse Hcc Models Guided By Driv...mentioning

confidence: 80%

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Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy

et al. 2023

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that show a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor‐κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK‐signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK‐STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 85%

Section: Construction Of Four Primary Mouse Hcc Models Guided By Driv...mentioning

confidence: 80%

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Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy

et al. 2023

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“…NSC305787 and NSC668394 are two inhibitors of ezrin that inhibit ezrin (Thr567) phosphorylation caused by PKCΙ primarily via their binding to ezrin ( Qureshi-Baig et al, 2020 ). Studies are currently being conducted to investigate the antitumor effects of these two compounds, particularly on osteosarcoma ( Shoaib et al, 2022 ), rhabdomyosarcoma ( Proudfit et al, 2020 ), pancreatic cancer ( Lipreri da Silva et al, 2022 ), and colon cancer ( Qureshi-Baig et al, 2020 ). In vitro , cell culture and interference also confirmed that NSC305787 reduced the cellular and malignant molecular behavior of CLL cell lines ( Lipreri da Silva et al, 2021 ).…”

Section: The Pharmacological Inhibition Of Ezrinmentioning

confidence: 99%

Ezrin expression in female reproductive tissues: A review of regulation and pathophysiological implications

Shi²,

Xu³

et al. 2023

Front. Cell Dev. Biol.

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Ezrin, a plasma membrane-microfilament linker, is a cytoskeletal organizer involved in many cellular activities by binding to the membrane protein-ezrin-cytoskeletal protein complex and regulating downstream signal transduction. Increasing evidence demonstrates that ezrin plays an important role in regulating cell polarity, proliferation and invasion. In this study, we analyzed the effects of ezrin on oocytes, follicle development, embryo development and embryo implantation. We reviewed the recent studies on the modalities of ezrin regulation and its involvement in the biological processes of female reproductive physiology and summarized the current research advances in ezrin inhibitors. These studies will provide new strategies and insights for the treatment of diseases.

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Inhibition of ezrin phosphorylation by NSC305787 attenuates procaterol-stimulated ciliary beating in airway cilia

Kawaguchi,

Yokoyama,

Wang

et al. 2024

Biochemical and Biophysical Research Communications

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NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells

Cited by 6 publications

References 36 publications

Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy

Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy

Ezrin expression in female reproductive tissues: A review of regulation and pathophysiological implications

Inhibition of ezrin phosphorylation by NSC305787 attenuates procaterol-stimulated ciliary beating in airway cilia

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