Morin Inhibits Proliferation and Induces Apoptosis by Modulating miR-188-5p/PTEN/AKT Regulatory Pathway in CML Cells

Nie, Zi-Yuan; Yang, Lin; Liu, Xiaojun; Yang, Zhan; Yang, Gao-Shan; Zhou, Jing; Qin, Yan; Yu, Jing; Jiang, Lingling; Wen, Jianbo; Luo, Jianmin

doi:10.2139/ssrn.3309394

Cited by 6 publications

(16 citation statements)

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“…STAT3 is essential for the leukemic potential of TKI-persistent LSC Since STAT3 and AKT were central nodes driving differential signaling in TKI-persistent K562, we evaluated their potential as therapeutic targets. Inhibition of AKT has previously been demonstrated to increase proliferation and apoptosis of CML LSCs but it also impairs maintenance, self-renewal and quiescence of normal HSCs, making it a difficult target [46,47]. Alternatively, STAT3 has been essential for initiating disease and TKI resistance in CML in an oncogene-independent manner [10][11][12].…”

Section: Resultsmentioning

confidence: 99%

Metabolic alterations mediated by STAT3 promotes drug persistence in CML

et al. 2021

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Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.

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Section: Resultsmentioning

confidence: 99%

Metabolic alterations mediated by STAT3 promotes drug persistence in CML

et al. 2021

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“…4a). BCR-ABL signaling mediates cell growth through multiple signaling pathways, including PI3K/Akt/mTOR (45,46) and Ras/MAPK (47). Therefore, the inhibition of signaling pathways affecting BCR-ABL after CXCR2 knockdown was investigated.…”

Section: Cxcr2 Inhibition Mediates Akt/mtor and C-myc Signaling Pathwaysmentioning

confidence: 99%

CXCR2 As a Novel Target for Overcoming Resistance to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Cells

Kim

Lee

Kang

et al. 2021

Preprint

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Background: Chronic myeloid leukemia (CML) is a reciprocal translocation disorder driven by a breakpoint cluster region (BCR)-Abelson leukemia virus (ABL) fusion gene that stimulates abnormal tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) are effective in the treatment of Philadelphia chromosome (Ph)+ CML patients. However, the appearance of TKI-resistant CML cells is a hurdle in CML treatment. Therefore, it is necessary to identify novel treatments that could target a different mechanism than that of tyrosine kinases.Methods: The study was designed to verify whether C-X-C chemokine receptor 2 (CXCR2) could be a novel target for TKI-resistant CML treatment. We examined CXCR2 ligands from CML patient samples and TKI-resistant CML cell lines. Then, we inhibited CXCR2 and examined the effects on cell proliferation and apoptosis using immunoblotting and flow cytometry. The CXCR2 inhibition effect was also confirmed using a mouse xenograft model with TKI-sensitive and -resistant CML cells.Results: Interleukin 8 (IL-8), a CXCR2 ligand, was significantly increased in the bone marrow serum of initially diagnosed CML patients. CML cell lines expressed CXCR2, regardless of their sensitivity to TKIs. IL-8 stimulated CXCR2, mTOR, and c-Myc mRNA expression in CML cell lines. CXCR2 antagonists suppressed the proliferation of CML cells via cell cycle arrest in the G2/M phase. In addition, CXCR2 inhibition attenuated mTOR, c-Myc, and BCR-ABL expression, leading to CML cell apoptosis, irrespective of TKI responsiveness. Moreover, SB225002, a CXCR2 antagonist, caused higher cell death in CML cells than TKIs. Using a mouse xenograft model, we confirmed that SB225002 suppresses CML cells, with a prominent effect on TKI-resistant CML cells.Conclusions: Taken together, our findings demonstrate that IL-8 is a prognostic factor to the progress of CML. Inhibiting the CXCR2-mTOR-c-Myc cascade is a promising therapeutic strategy to overcome TKI-sensitive and -insensitive CML. Thus, CXCR2 blockade is a novel therapeutic strategy to treat CML, and SB225002, a commercially available CXCR2 antagonist, might be a drug candidate to treat TKI-resistant CML.

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“…Therefore, the expression of downstream genes and proteins can be used to determine whether miRNAs were regulated by TD-tweezers. Therefore, we designed miRNA-34a-, miRNA-188-, miRNA-574-, and miRNA-152-related TD-tweezers and detected the expression of related mRNAs and proteins by PCR and Western blot (33)(34)(35). As can be seen in Fig.…”

Section: Living Cell Regulation Of Td-tweezersmentioning

confidence: 99%

Three-dimensional DNA tweezers serve as modular DNA intelligent machines for detection and regulation of intracellular microRNA

Zhou

Gao

et al. 2020

Sci. Adv.

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MicroRNAs (miRNAs) as novel biological targets are hardly applied in diagnostic and treatment of diseases, as they are difficult to be accurately detected and regulated. Here, we demonstrated a modular DNA intelligent machine named three-dimensional tweezers (TD-tweezers) to image and regulate miRNAs in living cells simultaneously. Fluorophore or miRNA inhibitors are introduced as detecting or regulating parts to construct different types of TD-tweezers, and the conformational state of TD-tweezers is controlled by the target miRNAs. The TD-tweezers exhibit excellent sensitivity, specificity, stability, and biocompatibility in vitro and in vivo, and their function of regulating miRNAs was confirmed by the up-regulated expression of downstream genes and proteins. Moreover, the TD-tweezers have been tested in whole blood, preliminarily verifying their clinical application potential. This design provides a multifunctional platform that can achieve efficient detection and regulation of targets within living cells and promote the development of DNA intelligent machines.

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Morin Inhibits Proliferation and Induces Apoptosis by Modulating miR-188-5p/PTEN/AKT Regulatory Pathway in CML Cells

Cited by 6 publications

References 0 publications

Metabolic alterations mediated by STAT3 promotes drug persistence in CML

Metabolic alterations mediated by STAT3 promotes drug persistence in CML

CXCR2 As a Novel Target for Overcoming Resistance to Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia Cells

Three-dimensional DNA tweezers serve as modular DNA intelligent machines for detection and regulation of intracellular microRNA

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