Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

Foster, John G.; Blunt, Matthew D.; Carter, Edward; Ward, Stephen G.

doi:10.1124/pr.110.004051

Cited by 108 publications

(74 citation statements)

References 272 publications

(311 reference statements)

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“…We previously showed that PI3Kd in synoviocytes is engaged downstream of the PDGF-R and regulates growth and survival via Akt activation (12). PI3Kd is also important for leukocyte chemotaxis in physiological and pathologic responses such as inflammation and hematologic malignancy (8,10,36,37). PI3Kd activity has been linked to cancer cell migration in breast cancer, neuroblastoma, and glioblastoma, and, aberrant expression of PI3Kd in tumors might contribute to the malignant properties of cancer cells (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

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Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Bartók

Hammaker

Firestein

2014

The Journal of Immunology

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Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA. PI3Kδ isoform was recently identified as a key regulator of FLS growth and survival, suggesting that it could contribute to synoviocyte aggressive behavior. Therefore, we assessed the role of PI3Kδ in RA synoviocyte migration and invasion. We observed that PI3Kδ inhibition or small interfering RNA knockdown decreased platelet-derived growth factor (PDGF)–mediated migration and invasion of FLS. We then showed that PI3Kδ regulates the organization of actin cytoskeleton and lamellipodium formation during PDGF stimulation. To gain insight into molecular mechanisms, we examined the effect of PI3Kδ inhibition on Rac1/PAK, FAK, and JNK activation. Our studies suggest that Rac1/PAK is key target of PDGF-mediated PI3Kδ signaling, whereas FAK and JNK are not involved. Thus, PI3Kδ contributes to multiple aspects of the pathogenic FLS behavior in RA. These observations, together with previous findings that PI3Kδ regulates FLS growth and survival, suggest that PI3Kδ inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion.

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Section: Discussionmentioning

confidence: 99%

“…PI3Ks control overlapping and nonredundant functions ranging from cell growth and proliferation to migration and cytokine expression (6,7). Perturbing this signaling cascade is implicated in inflammatory and autoimmune disorders as well as cancer (8)(9)(10)(11).…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Bartók

Hammaker

Firestein

2014

The Journal of Immunology

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“…Lack of PTEN protein was confirmed in all relevant cell lines (RPMI8402 expresses a mutant non-functioning allele) (Fig 1). An initial panel of compounds, including an inhibitor of all class 1 PI3Ks (PIK90) and selective inhibitors of p110 (TGX221), p110 (IC87114) and p110 (AS604850) (Foster et al, 2012), was used to investigate the effects of blocking PI3K activity on cell proliferation. Optimal concentrations that fully inhibit the relevant isoform(s) were used based on the literature and previous experiments (Foukas et al, 2010;Weigelt & Downward, 2012).…”

mentioning

confidence: 99%

Proliferation of PTEN‐deficient haematopoietic tumour cells is not affected by isoform‐selective inhibition of p110β PI3‐kinase and requires blockade of all class 1 PI3K activity

et al. 2013

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“…There is currently an intense focus by pharmaceutical companies to develop PI3K inhibitors as therapy for cancer, cardiovascular, respiratory, autoimmune and inflammatory diseases [14].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Blood Transcriptome in Patients With Chronic Kidney Disease of Uncertain Aetiology

Saravanabavan¹,

Magana-Arachchi²,

Gunarathne³

et al. 2016

International Conference on Bioscience and Biotechnology

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Chronic kidney disease of uncertain aetiology (CKDu) is an increasing health problem in certain agricultural regions of the tropical world including certain parts of Sri Lanka, Latin America, and India. This form of chronic kidney disease (CKD) does not have common causative factors such as diabetes or hypertension. The purpose of this study was to test the hypothesis that patients suffering with CKDu have differential expression patterns of genes in blood that will help differentiate them from healthy individuals, and to identify such differentially expressed genes as possible biomarkers of CKDu. Briefly, total RNA was isolated from peripheral whole blood of Stage 2, 3 and 4 CKDu patients in three different pools and compared to the expression pattern of a pooled sample of RNA extracted from healthy individuals. The RNA was amplified, reverse transcribed and hybridized to Illumina HumanHT-12 v4 Expression BeadChip arrays and scanned with an Illumina BeadArray Reader confocal scanner. Seven genes were identified that were commonly differentially expressed (fold change ≥ 2 or ≤ 0.5) in the three stages of CKDu population compared to healthy group. The genes identified included those involved in hypertensive response (ADM), gap junction channel activity (GJB4) and infectious/immune response (IFIT1, PI3, DEFA1, HBZ, RN7SK). These genes have the potential to be used as diagnostic markers of CKDu as they are differentially regulated in the studied stages of CKDu and can diagnose disease patients from the healthy individuals.

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Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

Cited by 108 publications

References 272 publications

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Proliferation of PTEN‐deficient haematopoietic tumour cells is not affected by isoform‐selective inhibition of p110β PI3‐kinase and requires blockade of all class 1 PI3K activity

Analysis of Blood Transcriptome in Patients With Chronic Kidney Disease of Uncertain Aetiology

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