Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts

Fan, Li; Yang, Huan; Zhang, Xinyu; Sun, Xianglin; Zhou, Jiamin; Li, Yuan; Liu, Yifei; Zhuang, Zhixiang; Wang, Guohua

doi:10.1177/15353702221076793

Cited by 4 publications

(2 citation statements)

References 37 publications

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“…The concept of cancer stem cells (CSC) has been proposed and generally accepted by the academic community. 14,15 With the continuous revelation of the roles of DHHC proteins in the field of stem cells, their function on tumor occurrence and progression has gradually attracted attention in recent years. Researchers began to study the role and mechanism of some members of DHHC proteins in the proliferation, metastasis, and apoptosis of tumor cells.…”

Section: Impact Statementmentioning

confidence: 99%

2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein

Wang,

Cui,

Chang

et al. 2023

Exp Biol Med (Maywood)

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Palmitoylation, which is mediated by protein acyltransferase (PAT) and performs important biological functions, is the only reversible lipid modification in organism. To study the effect of protein palmitoylation on hypopharyngeal squamous cell carcinoma (HPSCC), the expression levels of 23 PATs in tumor tissues of 8 HPSCC patients were determined, and high mRNA and protein levels of DHHC9 and DHHC15 were found. Subsequently, we investigated the effect of 2-bromopalmitate (2BP), a small-molecular inhibitor of protein palmitoylation, on the behavior of Fadu cells in vitro (50 μM) and in nude mouse xenograft models (50 μmol/kg), and found that 2BP suppressed the proliferation, invasion, and migration of Fadu cells without increasing cell apoptosis. Mechanistically, the effect of 2BP on the transduction of BMP, Wnt, Shh, and FGF signaling pathways was tested with qRT-PCR, and its drug target was explored with western blotting and acyl-biotinyl exchange assay. Our results showed that 2BP inhibited the transduction of the FGF/ERK signaling pathway. The palmitoylation level of Ras protein decreased after 2BP treatment, and its distribution in the cell membrane structure was reduced significantly. The findings of this work reveal that protein palmitoylation mediated by DHHC9 and DHHC15 may play important roles in the occurrence and development of HPSCC. 2BP is able to inhibit the malignant biological behaviors of HPSCC cells, possibly via hindering the palmitoylation and membrane location of Ras protein, which might, in turn, offer a low-toxicity anti-cancer drug for targeting the treatment of HPSCC.

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Section: Impact Statementmentioning

confidence: 99%

2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein

Wang,

Cui,

Chang

et al. 2023

Exp Biol Med (Maywood)

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“…Many of these proteins regulated by MSI1/MSI2 are involved in key signaling pathways that play essential roles in development and are abnormally activated in oncogenesis, such as maintenance of stem cell capacity and promotion of epithelial-mesenchymal transition (NUMB/NOTCH, PTEN/mTOR, TGFβ/SMAD3, MYC) [55,56]; it is thus unsurprising that elevated expression of MSI1/MSI2 has been observed in a broad spectrum of cancers [57][58][59][60][61][62][63][64]. In addition to their roles driving cancer initiation and progression, MSI1/MSI2 have also been implicated in conferring resistance to radiotherapy [65][66][67][68][69], chemotherapy [68,[70][71][72], and targeted therapies [73,74]. Collectively, these observations have positioned MSI1 and MSI2 as tantalizing targets for therapeutic intervention in cancer [55,75].…”

Section: Introductionmentioning

confidence: 99%

Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry

Bai

Adeshina

Bychkov

et al. 2023

Preprint

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RNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a "hotspot pharmacophore" from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of "hotspots" from protein-protein complexes to protein-RNA complexes, supports the "druggability" of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins.

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Dysregulated Stem Cell Markers Musashi-1 and Musashi-2 are Associated with Therapy Resistance in Inflammatory Breast Cancer

Haiduk

Sicking

Brücksken

et al. 2023

Archives of Medical Research

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Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts

Cited by 4 publications

References 37 publications

2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein

2-Bromopalmitate inhibits malignant behaviors of HPSCC cells by hindering the membrane location of Ras protein

Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry

Dysregulated Stem Cell Markers Musashi-1 and Musashi-2 are Associated with Therapy Resistance in Inflammatory Breast Cancer

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