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Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

ABSTRACT: Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5? (CA-MEK5?). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.

SUBMITTER: Paez-Mayorga J

PROVIDER: S-EPMC6135907 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

Paez-Mayorga Jesus J Chen Andrew L AL Kotla Sivareddy S Tao Yunting Y Abe Rei J RJ He Emma D ED Danysh Brian P BP Hofmann Marie-Claude C MC Le Nhat-Tu NT

Frontiers in cardiovascular medicine 20180906

Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ...[more]

PMID: 30238007

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Project description:Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells' function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with paeonol' effects are still not clear. Objective: Our study aimed to explain whether paeonol's protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs. Methods: ApoE-/- mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. miR-223 target gene was detected by double luciferase gene report test. Results: In vivo experiments confirmed that paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE-/- mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells. Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.

Dataset Information

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

Publications

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

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