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PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

ABSTRACT: Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

SUBMITTER: Wu W

PROVIDER: S-EPMC7085248 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

Wu Wenyi W Zhou Guohong G Han Haote H Huang Xionggao X Jiang Heng H Mukai Shizuo S Kazlauskas Andrius A Cui Jing J Matsubara Joanne Aiko JA Vanhaesebroeck Bart B Xia Xiaobo X Wang Jiantao J Lei Hetian H

Diabetes 20200108 4

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients ...[more]

PMID: 31915155

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Project description:IntroductionPI3K/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3Kδ/β/δ isoforms), PI3Kδ has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development/progression.MethodsOur previous studies revealed that PIK3CD-S is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3Kδ-S (encoded from PIK3CD-S) as a cancer biomarker and/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3Kδ isoforms were highly expressed in endocrine/solid tumor patient specimens and cell lines.ResultsDifferential PIK3CD-S/PIK3CD-L expression profiles were identified in a panel of endocrine/solid tumor cells. SiRNA knockdown of PIK3CD-L or PIK3CD-S differentially inhibits AKT/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of PTEN increased PI3Kδ levels and activated AKT/mTOR signaling, while overexpression of PTEN reduced PI3Kδ levels and inhibited AKT/mTOR signaling in cancer cells. Intriguingly, PI3Kδ-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3Kδ-L and its downstream AKT/mTOR signaling, while PI3Kδ-S promotes AKT/mTOR signaling without regulation by PTEN. Lastly, PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing endocrine/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3Kδ-L (but not PI3Kδ-S) mediated AKT/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT/mTOR signaling. In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells.ConclusionIn summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

Project description:PurposeNeovascular eye diseases, such as proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (wAMD) and retinopathy of prematurity (ROP), are major causes of vision loss and blindness worldwide. Our transcription factor motif enrichment analysis highlighted RUNX1 as a key regulator in the hypoxic response. The purpose of this study was to characterize how loss of Runx1 affects physiological and pathological retinal vasculature formation.MethodsRNA-seq analysis and Transcription factor motif enrichment analysis were conducted in hypoxic and normoxic HUVECs. Conditional deletion of Runx1 in endothelial cells In mice was achieved using recombinase driver Cdh5-CreERT2. Vascular coverage, density, vessel progression, branchpoints, and sprout numbers was measured in retina of Runx1iECKO mice. The expression patterns, functions, and potential therapeutic value of RUNX1 were further explored with clinical samples, as well as in vivo and in vitro experiments. Bioinformatics and high-throughput sequencing were performed to identify potential target genes of Runx1. RT-qPCR and Western blot analyses were carried out to detect the changes of PI3-kinase/AKT/mTOR pathway.ResultsLoss of Runx1 in mice resulted in a reduction of the vascular coverage, density, vessel progression, branchpoints, and sprouts numbers of the retinal vascular network during its development. Notably, mature blood vessels remained unaffected by Runx1 inhibition. Upregulation of RUNX1 was observed in patients with PDR and ROP. RUNX1 Inhibition reduced endothelial cell proliferation, migration and tubule formation, leading to decreased pathological neovascularization, which is shown in oxygen-induced retinopathy. Mechanistically, in vitro experiments demonstrated that RUNX1 regulates EC angiogenesis through the PI3K/AKT/mTOR signaling pathway.ConclusionsRunx1 is essential for physiological retinal vascularization. RUNX1 Inhibition may effectively decrease pathological neovascularization. Our findings suggest that targeting RUNX1 could be a promising therapeutic strategy for retinal neovascular disorders, preserving the integrity of mature blood vessels while selectively inhibiting neovascularization.

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PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

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PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

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