Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway

Niu, Chunping; Zhao, Chen; Ye, Zhong; Zhang, Xiaoli; Pan, Jing; Si, Weike

doi:10.1186/s12935-014-0074-z

Cited by 20 publications

(30 citation statements)

References 49 publications

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“…It was recently reported that the level of Cyr61 is increased in BM supernatants from patients with ALL, and this change could promote ALL cell survival (22). Previous studies showed that BM stromal cells are the major source of Cyr61 (21,32). Our current study showed that Cyr61 was overexpressed not only in the BMMNCs from patients with ALL, but also two ALL cell lines.…”

Section: Discussionsupporting

confidence: 57%

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

Cao

Song

et al. 2018

Int J Mol Med

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Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara-C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara-C-induced apoptosis of ALL cells, and its function was blocked by the use of the anti-Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl-2 in Ara-C-treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara-C partially via the NF-κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF-κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.

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Section: Discussionsupporting

confidence: 57%

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

Cao

Song

et al. 2018

Int J Mol Med

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“…CYR61 is a connective tissue growth factor which has been considered as a crucial mediator in the developing and metastasis of cancers [26]. High expression of CYR61 was present in cervical cancer [27] and oesophageal squamous cell carcinoma [28], and exerted diverse functions in several types of cancers [29]. In malignant melanoma, CYR61 worked as a biomarker for tumour cells proliferation and metastasis, making it a potential target for melanoma treatment [30].…”

Section: Discussionmentioning

confidence: 99%

KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

Peng

Zou

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Since DNA damage is a first incident occurred during a tumour attack, it is rational that histone H2A.X phosphorylation on tyrosine 39 (H2A.X Y39ph) may act as a tumour-relevant factor. This study was aimed to test the authenticity of the hypothesis. Uveal melanoma MP65 cells were transfected for expression of KRas mutated. H2A.X phosphorylation and ERK1/2 was measured, and transwell experiment was performed to examine the consequents of H2A.X Y39ph on MP65 cells developing and migration. Regulatory relationship between H2A.X Y39ph and ERK1/2 downstream genes were measured. Moreover, whether JMJD6 and MDM2 are involved in H2A.X phosphorylation was studied. Mutation of Ras activated ERK1/ 2 signalling and inhibited H2A.X phosphorylation at Y39. Silence of H2A.X Y39ph contributed to the regulation of MP65 cells growth, migration and transcription of ERK1/2 downstream genes, including CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16. The repressed H2A.X phosphorylation through Ras-ERK1/2 signalling might be through MDM2-mediated JMJD6 degradation. Our study suggested that Ras-ERK1/2 signalling inhibited H2A.X phosphorylation at Y39, which led to the uncontrolled developing and migration of uveal melanoma cells. In addition, H2A.X phosphorylation was mediated possibly through JMJD6 which could be degraded by MDM2.

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“…As expected, the NF‐κB pathway contributed to the anti‐apoptotic function of Cyr61. Recent evidence suggests that Cyr61 mediates ALL and AML cell survival by the AKT pathway and by the ERK1/2 pathway, respectively; however, we found that AKT and ERK1/2 were not involved in the ability of Cyr61 to inhibit the apoptosis of CML cells induced by IM. Further analysis showed that Cyr61 treatment led to strong activation of NF‐κB signaling as well as Bcl‐2 production.…”

Section: Discussioncontrasting

confidence: 85%

Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway

Song

Cai

et al. 2019

Cancer Science

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Although the targeted tyrosine kinase inhibitor imatinib mesylate (IM) has achieved significant responses against CML in the clinical setting, a small proportion of patients fail to respond to IM treatment and their disease continues to progress, indicating resistance to IM therapy. As a secreted extracellular matrix protein, cysteine‐rich protein 61 (Cyr61) plays an important role in the resistance of solid tumors to chemotherapy, but its role in CML is unclear. In the present study, we observed that Cyr61 levels were upregulated in the plasma and bone marrow (BM) of patients with CML as well as in K562 cells. This upregulation of Cyr61 significantly decreased IM‐induced cellular apoptosis of K562 cells through nuclear factor kappa B/B‐cell lymphoma 2 pathways. Inhibition of Cyr61 restored the chemosensitivity of K562 cells to IM both in vitro and in vivo. Thus, our results showed for the first time that Cyr61 plays an important role in regulating the chemosensitivity of CML cells to IM, suggesting that selectively targeting Cyr61 directly or its relevant effector pathways may provide potential value in improving the clinical response of patients with CML to IM treatment.

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Inhibiting CCN1 blocks AML cell growth by disrupting the MEK/ERK pathway

Cited by 20 publications

References 49 publications

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation

KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway

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