Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells

Go, Young Hyun; Lim, Changjin; Jeong, Ho-Chang; Kwon, Ohseong; Chung, Sung-Kyun; Lee, Haeseung; Kim, Wankyu; Suh, Young Ger; Son, Woo Sung; Lee, Mi Ok; Cha, Hyuk‐Jin; Kim, Seok Ho

doi:10.3389/fchem.2019.00298

Cited by 12 publications

(11 citation statements)

References 38 publications

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“…The survival advantage of culture-adapted hESCs under mitotic stress Culture-adapted hESCs become highly resistant to various stressors, such as DNA damage 10 , single-cell dissociation, and YM155 8 , 'a stemtoxic agent' that selectively induces death in undifferentiated pluripotent stem cells 13 through cellular uptake by SLC35F2, a solute carrier protein 27,28 . In addition to the increased survival of hESCs under genotoxic stress, escape from cell death during mitosis has been suggested to increase aneuploidy during long-term culture 9 .…”

Section: Resultsmentioning

confidence: 99%

TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

Kim

Jeong

et al. 2023

Exp Mol Med

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Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of BCL2L1, which is in locus 20q11.21. In this study, we demonstrated that the expression of TPX2, a gene located in 20q11.21, led to BCL2L1 induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent BCL2L1 expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture.

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Section: Resultsmentioning

confidence: 99%

TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

Kim

Jeong

et al. 2023

Exp Mol Med

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“…Thus, it is necessary to eliminate the undifferentiated iPSCs without harming differentiated cells in a cell mixture prior to cell transplantation. Considerable efforts have been spent on developing approaches to eliminate residual undifferentiated iPSCs − for the safe clinical applications of iPSC-based cell therapy, but current strategies still have many drawbacks. Therefore, it is still necessary to develop an innovative strategy that is rapid (=< 2 h), effective, and general for eliminating undifferentiated iPSCs in cell mixtures.…”

Section: Introductionmentioning

confidence: 99%

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

et al. 2021

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Tumorigenic risk of undifferentiated human induced pluripotent stem cells (iPSCs), being a major obstacle for clinical application of iPSCs, requires novel approaches for selectively eliminating undifferentiated iPSCs. Here, we show that an l-phosphopentapeptide, upon the dephosphorylation catalyzed by alkaline phosphatase (ALP) overexpressed by iPSCs, rapidly forms intranuclear peptide assemblies made of α-helices to selectively kill iPSCs. The phosphopentapeptide, consisting of four l-leucine residues and a C-terminal l-phosphotyrosine, self-assembles to form micelles/nanoparticles, which transform into peptide nanofibers/nanoribbons after enzymatic dephosphorylation removes the phosphate group from the l-phosphotyrosine. The concentration of ALP and incubation time dictates the morphology of the peptide assemblies. Circular dichroism and FTIR indicate that the l-pentapeptide in the assemblies contains a mixture of an α-helix and aggregated strands. Incubating the l-phosphopentapeptide with human iPSCs results in rapid killing of the iPSCs (=<2 h) due to the significant accumulation of the peptide assemblies in the nuclei of iPSCs. The phosphopentapeptide is innocuous to normal cells (e.g., HEK293 and hematopoietic progenitor cell (HPC)) because normal cells hardly overexpress ALP. Inhibiting ALP, mutating the l-phosphotyrosine from the C-terminal to the middle of the phosphopentapeptides, or replacing l-leucine to d-leucine in the phosphopentapeptide abolishes the intranuclear assemblies of the pentapeptides. Treating the l-phosphopentapeptide with cell lysate of normal cells (e.g., HS-5) confirms the proteolysis of the l-pentapeptide. This work, as the first case of intranuclear assemblies of peptides, not only illustrates the application of enzymatic noncovalent synthesis for selectively targeting nuclei of cells but also may lead to a new way to eliminate other pathological cells that express a high level of certain enzymes.

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“…SLC35F2 can be used as a biomarker of susceptibility to YM155, which is a therapy for prostate cancer 11. SLC35F2 can promote the entry of YM155 into human pluripotent stem cells (hPSCs) and can act as a stem cell toxin 12. Other solute carrier family members, such as SLC12A5 and SLC34A2, are highly expressed in BC 13.…”

Section: Introductionmentioning

confidence: 99%

<p>Knockdown of SLC35F2 Inhibits the Proliferation and Metastasis of Bladder Cancer Cells</p>

Chen¹,

Gào²,

Huang³

et al. 2019

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Background: Many studies have shown that solute carrier family 35 member F2 (SLC35F2) plays a key role in the biological processes of multiple cancers. However, there have been no reports on the role of SLC35F2 in the occurrence and development of bladder cancer (BC). Methods: SLC35F2 expression data and clinical and prognostic information from BC patients were obtained from databases. SLC35F2 expression in BC was verified by quantitative real-time PCR (qRT-PCR). The influence of SLC35F2 knockdown on the proliferation, apoptosis, migration and invasion in the 5637 and T24 cell lines was studied, and tumor formation experiments were performed in nude mice. Gene set enrichment analysis (GSEA) was used to predict the pathways and functions of SLC35F2 in BC. Results: SLC35F2 was highly expressed in BC tissues and was associated with invasiveness and T stage in BC patients. SLC35F2 knockdown can inhibit the proliferation, migration and invasion of BC cells and can promote apoptosis. SLC35F2 knockdown significantly reduced tumorigenesis in nude mice. GSEA showed that BC, pathways in cancer, apoptosis and the P53 signaling pathway were significantly enriched in SLC35F2 high expression phenotype. Conclusion: SLC35F2 can promote malignant progression and is a potential therapeutic target in BC.

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Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells

Cited by 12 publications

References 38 publications

TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

Enzymatically Forming Intranuclear Peptide Assemblies for Selectively Killing Human Induced Pluripotent Stem Cells

<p>Knockdown of SLC35F2 Inhibits the Proliferation and Metastasis of Bladder Cancer Cells</p>

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