Knockdown of CypA inhibits interleukin-8 (IL-8) and IL-8-mediated proliferation and tumor growth of glioblastoma cells through down-regulated NF-κB

Sun, Shanshan; Wang, Qiuwei; Giang, An-Hoa; Cheng, Cong; Soo, Chia; Wang, Cun‐Yu; Liau, Linda M.; Chiu, Robert

doi:10.1007/s11060-010-0220-y

Cited by 48 publications

(39 citation statements)

References 34 publications

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“…However, the functional role of the closely related PPIase family member CypA (PPIA) in skeletal development remains elusive. In previous reports, we demonstrated a close relationship between CypA and NF-B signaling (22,28). NF-B was found to regulate certain aspects of endochondral ossification during embryogenesis (29,30).…”

Section: Discussionmentioning

confidence: 68%

“…We had previously demonstrated that CypA knockdown (Kd) results in the downregulation of NF-B/p65 (RelA, a subunit of NF-B) in glioblastoma cell lines and a murine myoblast line, C2C12 (22,28). Decreased NF-B/p65 expression levels were also observed in CypA Kd mouse chondrogenic ATDC5 stable clones, 2T7 and 2T3, as well as in CypA KO mouse proximal tibia growth plates ( Fig.…”

Section: Effect Of Cypa Deficiency On Chondrocyte Differentiation In mentioning

confidence: 89%

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Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Guo

Shen

Kwak

et al. 2015

Molecular and Cellular Biology

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g Recent studies showed that cyclophilin A (CypA) promotes NF-B/p65 nuclear translocation, resulting in enhanced NF-B activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of CypA in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in CypA knockdown chondrogenic cells than in wild-type cells, indicating that CypA plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that CypA is needed for chondrogenic differentiation. Newborn CypAdeficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while highresolution micro-computed tomography ( Chondrogenesis is an essential process in vertebrates. It leads to the formation of cartilage growth plates, thereby driving bodily growth while providing structural templates and induction signals for the formation of long bones through endochondral ossification (1). On the other hand, defects in chondrogenesis cause various chondrodysostoses and chondrodysplasias, with such skeletal malformations accounting for a significant proportion of human birth defects that often result in embryonic and perinatal lethality (2). To identify the molecular mechanisms that drive chondrocyte differentiation and impact underlying cartilage diseases, the transcriptional mechanisms governing their cartilage-specific expression have been intensely studied. As a general overview, the chondrocyte differentiation pathway corresponds to a succession of major genetic program switches that are likely controlled by a specific set of transcriptional activators, repressors, and associated factors. While some of these factors play essential roles in determining cell fate and differentiation, other factors are found to be mutated in severe diseases of cartilage and bone malformation (3). The framework of the cartilage matrix is a collagen fiber network comprised primarily of type II collagen (Col2) (encoded by the Col2␣1 gene) and secondarily of type IX collagen (encoded by Col9␣1, Col9␣2, and Col9␣3). Collagen type X (Col10) (encoded by Col10␣1) is also produced in abundance, but exclusively by prehypertrophic and hypertrophic chondrocytes (2).Importantly, chondrocyte differentiation requires Sox family transcription factors in the early stages and Runx2 in the late stages (4, 5). In particular, Sox9 has an essential, nonredundant role in specifying the commitment and differentiation of mesenchymal cells toward the chondrogenic lineage in all developing skeletal elements. While Sox9 is turned on in chondrogenic and osteogenic mesenchymal cells prior to condensation and remains highly expressed in prechondrocytes...

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Section: Discussionmentioning

confidence: 68%

Section: Effect Of Cypa Deficiency On Chondrocyte Differentiation In mentioning

confidence: 89%

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Guo

Shen

Kwak

et al. 2015

Molecular and Cellular Biology

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“…For example, the stability, localisation and activity of the p65 subunit of NF-κB was recently shown to be regulated by association with CypA because its downregulation impaired production of NF-κB-induced cytokines while reducing the proliferation of glioblastoma cells. 32,33 Similar to CypA, genetic ablation of CypB reduces glioma cell survival and proliferation, as shown both in vitro and in vivo. 34,35 We found that multiple cyclophilins -CypA, CypB and CypH -directly interact with a newly identified target, p38MAPK, facilitating isomerisation of Pro224, which in turn is required to regulate phosphorylation of kinase regulatory Thr-Gly-Tyr motif.…”

Section: Discussionmentioning

confidence: 94%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.

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“…S4A), and so was used for the calculation of a radial distribution function. At this point, cells have had time to migrate (18) and are adherent. One might ask why the cells would migrate in the bulk culture, whereas they are not observed to move on the SCBC platform.…”

Section: Predicting Spatial Distributions Of Gbm Cells From the Measuredmentioning

confidence: 99%

Glioblastoma cellular architectures are predicted through the characterization of two-cell interactions

Kravchenko‐Balasha

Wang

Remacle

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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To understand how pairwise cellular interactions influence cellular architectures, we measured the levels of functional proteins associated with EGF receptor (EGFR) signaling in pairs of U87EGFR variant III oncogene receptor cells (U87EGFRvIII) at varying cell separations. Using a thermodynamics-derived approach we analyzed the cell-separation dependence of the signaling stability, and identified that the stable steady state of EGFR signaling exists when two U87EGFRvIII cells are separated by 80-100 μm. This distance range was verified as the characteristic intercellular separation within bulk cell cultures. EGFR protein network signaling coordination for the U87EGFRvIII system was lowest at the stable state and most similar to isolated cell signaling. Measurements of cultures of less tumorigenic U87PTEN cells were then used to correctly predict that stable EGFR signaling occurs for those cells at smaller cell-cell separations. The intimate relationship between functional protein levels and cellular architectures explains the scattered nature of U87EGFRvIII cells relative to U87PTEN cells in glioblastoma multiforme tumors.GBM | surprisal analysis | cancer cell-cell signaling | biological steady state | two-body cell-cell interaction P athological analysis of tumor tissues is typically led by the analyses of cellular architectures within those tumors. Relationships between those architectures and molecular biomarkers of disease are often poorly understood. We seek to establish such a relationship, starting from physical principles. We take as an example glioblastoma multiforme (GBM) cancer cells that express the EGF receptor (EGFR) variant III oncogene receptor (EGFRvIII). Although these cells enhance tumorigenicity, invasion, and other hallmarks of cancer (1, 2), they comprise only a subpopulation of the cancer cells within an EGFRvIII+ tumor, and their distribution is diffuse (1, 3, 4). To help understand this diffuse cellular architecture, we developed an experimentaltheoretical methodology based on analysis of EGFR signaling in two interacting cells. In many physical systems-from planets to atomic solids-the interactions of an element of that system with its surroundings can be understood within the context of two-body interactions. This broad observation inspired our experimental approach, which was to measure EGFR-associated signaling activity in statistically significant numbers of two EGFRvIII+ GBM cells, as a function of intercellular separation. Our theoretical approach was similarly inspired: it assumed that the resultant two-cell data sets could be interpreted using thermodynamic-like considerations.Our approach allows a determination of the stability of a phosphoprotein signaling network in two interacting cells, and demonstrates how that stability dictates the cell-cell distance distribution in a bulk culture. Using this concept we determined the most probable intercellular separation distance range within cell populations, and the deviations thereof. The available literature suggests our conclusion...

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Knockdown of CypA inhibits interleukin-8 (IL-8) and IL-8-mediated proliferation and tumor growth of glioblastoma cells through down-regulated NF-κB

Cited by 48 publications

References 34 publications

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Glioblastoma cellular architectures are predicted through the characterization of two-cell interactions

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