Musashi-2 Silencing Exerts Potent Activity against Acute Myeloid Leukemia and Enhances Chemosensitivity to Daunorubicin

Han, Yantao; Ye, Aifang; Zhang, Yan; Zhang, Cai; Wang, Wei; Sun, Li; Jiang, Songfu; Wu, Jianbo; Kang, Yu; Zhang, Shenghui

doi:10.1371/journal.pone.0136484

Cited by 33 publications

(36 citation statements)

References 33 publications

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“…Nowadays, few studies report the association of MSI2 with drug resistance, and the corresponding mechanisms are poorly understood. MSI2 silencing exhibits markedly higher proliferation‐inhibiting rates and enhances daunorubicin‐induced cell apoptosis in Dami cells and primary AML cells (40). The gene expression profile in the two clusters of small‐cell lung cancer cells [poly(ADP) ribose polymerase inhibitor sensitive vs. insensitive] before and after exposure to cisplatin and veliparib revealed a panel of 5 genes that are restricted to the sensitive cell lines (including MSI2) (41).…”

Section: Discussionmentioning

confidence: 99%

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

et al. 2017

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Our earlier work showed that Musashi (MSI)-2 promoted the development of pancreatic cancer (PC) by down-regulating Numb, which prevented murine double-minute (MDM)-2-mediated p53 ubiquitin degradation. Thus, we investigate the relationship among MSI2, Numb, MDM2, and p53 in PC and, an association that has not been reported to our knowledge. MSI2 had no relationship with mutant p53 (mtp53) and wild-type p53 (wtp53) in normal PC cells. However, in response to gemcitabine or cisplatin treatment, MSI2 silencing simultaneously down-regulated MDM2 and up-regulated Numb and wtp53 protein levels. Moreover, these 4 endogenous proteins can be coimmunoprecipitated as a quaternary complex. Numb small interfering RNA (siRNA) reversed the MSI2 silencing-induced p53 increase. During treatment with chemical agents, MSI2 silencing decreased drug resistance and cell motility and inhibited tumor growth, all of which were significantly reversed by p53 siRNA. MSI2 was also negatively associated with Numb and positively associated with MDM2 expression in tissue. Overexpression of MSI2, MDM2, and mtp53 and weak expression of Numb were closely associated with aggressive clinicopathologic characteristics and poor prognosis for patients with PC. MSI2 negatively regulates wtp53 protein by up-regulating MDM2 and down-regulating Numb after treatment with chemical agents. MSI2 promotes drug resistance and malignant biology of PC in a p53-dependent manner.-Sheng, W., Dong, M., Chen, C., Wang, Z., Li, Y., Wang, K., Li, Y., Zhou, J. Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

et al. 2017

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“…As some examples, elevated expression of MSI2 induced resistance to paclitaxel in ovarian cancer cells in vitro (27). MSI2 silencing in AML cells sensitized these cells to treatment with daunorubicin, accompanied by induction of cell cycle arrest and induction of apoptosis, mediated by downregulation of BCL2 and upregulation of BAX (35). MSI1 was recently described as a regulator of response to radiation therapy in glioblastoma.…”

Section: Musashi Proteins In Tumor Responses To Chemotherapy and Radimentioning

confidence: 99%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

213

240

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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as regulators of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers, glioblastoma, and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target.

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“…As such, it mediates mRNA stability and translation of proteins involved in oncogenic pathways . Overexpression and knockdown studies indicate that MSI2 is a promising therapeutic target for cancer …”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20] Overexpression and knockdown studies indicate that MSI2 is a promising therapeutic target for cancer. 3,13,16,21,22 Human MSI2 is a 328 amino acid protein that contains two RNA recognition motifs (RRMs) spanning G21-K111 (RRM1) and K110-P187 (RRM2). A BLAST 23 search revealed that MSI2 (residues F I G U R E 1 Clustal multiple sequence alignment of human MSI2, human MSI1, and mouse MSI1.…”

Section: Introductionmentioning

confidence: 99%

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

et al. 2019

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Musashi‐2 (MSI2) belongs to Musashi family of RNA binding proteins (RBP). Like Musashi‐1 (MSI1), it is overexpressed in a variety of cancers and is a promising therapeutic target. Both MSI proteins contain two N‐terminal RNA recognition motifs and play roles in posttranscriptional regulation of target mRNAs. Previously, we have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2‐specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2‐RRM1, the key motif that is responsible for the binding. Here, we report the crystal structure and the first NMR solution structure of MSI2‐RRM1, and compare these to the structures of MSI1‐RBD1 and other RBPs. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2‐RRM1 shows a highly similar overall folding topology to MSI1‐RBD1 and other RBPs. The structural information of MSI2‐RRM1 will be helpful for understanding MSI2‐RNA interaction and for guiding rational drug design of MSI2‐specific inhibitors.

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Musashi-2 Silencing Exerts Potent Activity against Acute Myeloid Leukemia and Enhances Chemosensitivity to Daunorubicin

Cited by 33 publications

References 33 publications

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

Cooperation of Musashi‐2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Crystal and solution structures of human oncoprotein Musashi‐2 N‐terminal RNA recognition motif 1

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