Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells

Wang, Fengfei; Zhou, Shuang; Qi, Dan; Xiang, Shi Hua; Wong, Eric T.; Wang, Xuejing; Fonkem, Ekokobe; Hsieh, Tze Chen; Yang, Jianhua; Kirmani, Batool F.; Shabb, John B.; Wu, Joseph M.; Wu, Min; Huang, Jason H.; Yu, Wei; Wu, Erxi

doi:10.1021/jacs.8b12872

Cited by 40 publications

(42 citation statements)

References 46 publications

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“…Finally, a recent study identified nucleolin as the functional binding target of Sal. The drug inhibited the transcription of the nucleolin gene (NCL) and led to a suppression of downstream CD34 gene expression [70], which was also shown in our RNA-seq data.…”

Section: Discussionsupporting

confidence: 85%

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

et al. 2020

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Background: Tumors are heterogeneous in nature, composed of different cell populations with various mutations and/or phenotypes. Using a single drug to encounter cancer progression is generally ineffective. To improve the treatment outcome, multiple drugs of distinctive mechanisms but complementary anticancer activities (combination therapy) are often used to enhance antitumor efficacy and minimize the risk of acquiring drug resistance. We report here the synergistic effects of salinomycin (a polyether antibiotic) and dasatinib (a Src kinase inhibitor). Methods: Functionally, both drugs induce cell cycle arrest, intracellular reactive oxygen species (iROS) production, and apoptosis. We rationalized that an overlapping of the drug activities should offer an enhanced anticancer effect, either through vertical inhibition of the Src-STAT3 axis or horizontal suppression of multiple pathways. We determined the toxicity induced by the drug combination and studied the kinetics of iROS production by fluorescence imaging and flow cytometry. Using genomic and proteomic techniques, including RNA-sequencing (RNA-seq), reverse transcriptionquantitative polymerase chain reaction (RT-qPCR), and Western Blot, we subsequently identified the responsible pathways that contributed to the synergistic effects of the drug combination. Results: Compared to either drug alone, the drug combination showed enhanced potency against MDA-MB-468, MDA-MB-231, and MCF-7 human breast cancer (BC) cell lines and tumor spheroids. The drug combination induces both iROS generation and apoptosis in a time-dependent manner, following a 2-step kinetic profile. RNA-seq data revealed that the drug combination exhibited synergism through horizontal suppression of multiple pathways, possibly through a promotion of cell cycle arrest at the G1/S phase via the estrogen-mediated S-phase entry pathway, and partially via the BRCA1 and DNA damage response pathway.

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Section: Discussionsupporting

confidence: 85%

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

et al. 2020

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“…CD44 exists as a large family of isoforms, produced by the alternative splicing of up to 20 exons, and CD44v6, in particular, is required for CSCs migration and generation of metastatic tumors 44 . Tumor spheres co-expressed other NB stem cells marker proteins such as CD114 23,24 and NCL 25 and the nucleolar antigens NPM1 40 and PES1 42 , as well as GPC2, that is an oncoprotein strongly candidate to be an immunotherapeutic target in NB 41 . While studying embryonic antigens in neurospheres, we discovered that they expressed the stem cell marker N-Cadherin and the embryonic morphogen Nodal (Fig.…”

Section: Resultsmentioning

confidence: 99%

Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma

Ognibene

Pezzolo

2020

Sci Rep

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Neuroblastoma, an embryonic tumor arising from neuronal crest progenitor cells, has been shown to contain a population of undifferentiated stem cells responsible for the malignant state and the unfavorable prognosis. Although many previous studies have analyzed neuroblastoma stem cells and their therapeutic targeting, this topic appears still open to novel investigations. Here we found that neurospheres derived from neuroblastoma stem-like cells showed a homogeneous staining for several key nucleolar proteins, such as Nucleolin, Nucleophosmin-1, Glypican-2 and PES-1. We investigated the effects of Roniciclib (BAY 1000394), an anticancer stem cells agent, on neurospheres and on an orthotopic neuroblastoma mouse model, discovering an impressive inhibition of tumor growth and indicating good chances for the use of Roniciclib in vivo. We demonstrated that Roniciclib is not only a Wnt/β-catenin signaling inhibitor, but also a nucleolar stress inducer, revealing a possible novel mechanism underlying Roniciclib-mediated repression of cell proliferation. Furthermore, we found that high expression of Nucleophosmin-1 correlates with patients' short survival. The co-expression of several stem cell surface antigens such as CD44v6 and CD114, together with the nucleolar markers here described, extends new possibilities to isolate undifferentiated subpopulations from neuroblastoma and identify new targets for the treatment of this childhood malignancy. Neuroblastoma (NB) is an embryonic pediatric tumor that originates from neural crest progenitors cells 1,2. NB is the most common tumor in young children, about the 90% of cases happen in children less than 5 years old 3. NB is characterized by clinical, biologic and genomic remarkable heterogeneity that affected the survival of NB patients despite intensive therapy 4,5. Cancer stem cells (CSCs) are suggested to be responsible for drug resistance and relapse due to their ability to self-renew, and to differentiate into heterogeneous lineages of cancer cells 6. Heterogeneity within a given cancer arises from diverse cell types recruited to the tumor, and from genetic or epigenetic differences among the cancer cells themselves 7,8. CSCs are the exclusive sources of all tumor cells, survive and persist after cancer therapy and are responsible for tumor relapse and metastasis 9. The concept of CSCs has immediate therapeutic consequences: if cancer growth is sustained by CSCs, then curative therapy will require targeting of this specific sub-population 10. The clinical presentation and the treatment response of advanced NB, which results in relapse and a refractory state after a good response to the initial chemotherapy, suggests the possibility that CSCs exist in NB tumors 11. Moreover, the heterogeneity of NB tumor histology and biology may suggest the existence of selfrenewing multipotent CSCs 12. NB tumors with unfavorable prognosis have been shown to contain a population of undifferentiated stem cells responsible for their malignant state 13. Putative CSCs identification in prima...

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“…[100,101] Furthermore,western blots and microscopy experiments revealed features of lysosomal degradation of iron-binding proteins that led to lysosomal and lipid reactive oxygen species (ROS) and lysosomal membrane permeabilization. [104] Thei nv itro studies performed in the 1970s,o nw hich we base the use of ionophores as cell biological tools,d on ot capture the complexity of cellular systems having ap lethora of ion gradients that are often interrelated. [102,103] Interestingly,t he Rodriguez lab found that cell death by salinomycin could be blocked by the ferroptosis inhibitors N-acetylcysteine,ferrostatin-1, and deferoxamine,w hich made the team conclude that salinomycin induced ferroptosis to selectively target CSCs.C ollectively,t hese studies demonstrate that chemical derivatization of ionophores can enable the discovery of critical mechanistic details.V ery recently,n ucleolin was identified as adirect and functionally relevant binding protein of salinomycin in neuroblastoma cell lines.T his interesting observation may shed additional light on how salinomycin exerts its inhibitory effects against CSCs and it furthermore underscores that cellular activities not involving ion transport are entirely possible for the carboxyl polyether ionophores.…”

Section: Methodsmentioning

confidence: 99%

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

2019

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Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells

Cited by 40 publications

References 46 publications

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

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