Clusterin: a key player in cancer chemoresistance and its inhibition

Koltai, Tomas

doi:10.2147/ott.s58622

Cited by 139 publications

(116 citation statements)

References 65 publications

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“…We identified a total of 399 proteins, mostly related to adhesion and the cytoskeleton (Supplementary Table S4), indicating that there were microvesicle-like exosomes in the NCI-H2052 supernatant. Among the 399 supernatant proteins, interleukin-8 (IL-8), 16 growth-regulated α-protein (GROα), 16 midkine (MK), 17 IL-18, 18 IL-6, 19 hepatoma-derived growth factor (HDGF), 20 clusterin (CLU) 21 and granulin (GRN) 22 are known to be involved in tumor angiogenesis. We examined the involvement of IL-8, GROα, IL-18 and IL-6 in tube formation induced by the NCI-H2052 supernatant using commercially available neutralizing antibodies corresponding to each of the above proteins or protein receptors.…”

Section: Resultsmentioning

confidence: 99%

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Eguchi

Nakano²,

Wakabayashi³

2016

Oncogene

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Malignant mesothelioma is an aggressive tumor arising from the mesothelial cells of serous membranes and is associated with tumor angiogenesis, which is a prerequisite for tumor progression. Vascular endothelial growth factors (VEGFs) including VEGF-A have a crucial role in tumor angiogenesis. However, bevacizumab, a monoclonal antibody to VEGF-A, has recently been reported not to improve the progression-free survival of patients with malignant mesothelioma. Cell culture supernatant contains extracellular components such as serum, which can mask the existence of unknown cell-derived factors in the supernatant and make it difficult to detect the factors by subsequent protein analysis. We tried using serum-free culture for human mesothelioma cell lines, NCI-H28, NCI-H2452 and NCI-H2052, and only NCI-H2052 cells adapted to serum-free culture. We found that serum-free culture supernatant derived from NCI-H2052 cells induces the formation of capillary-like tube structures (tube formation) in three-dimensional culture, in which endothelial cells sandwiched between two layers of collagen or embedded in collagen are incubated with various angiogenic inducers. However, neither neutralization of VEGF-A nor RNA interference of VEGF receptor 2 (VEGFR2) suppressed the supernatant-induced tube formation. Using mass spectrometry, we identified a total of 399 proteins in the supernatant, among which interleukin-8 (IL-8), growth-regulated α-protein, midkine, IL-18, IL-6, hepatoma-derived growth factor, clusterin and granulin (GRN), also known as progranulin (PGRN), were included as a candidate protein inducing angiogenesis. Neutralizing assays and RNA interference showed that PGRN, but not the above seven candidate proteins, caused the supernatant-induced tube formation. We also found that NCI-H28 and NCI-H2452 cells express PGRN. Furthermore, we demonstrate that not only PGRN but also GRN-like protein have an important role in the supernatant-induced tube formation. Thus, mesothelioma-derived GRNs induce VEGF-independent angiogenesis.

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Section: Resultsmentioning

confidence: 99%

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Eguchi

Nakano²,

Wakabayashi³

2016

Oncogene

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“…This multifunctional protein is associated with clearance of cellular debris and apoptosis, as well as with lipid transport, membrane recycling, cell adhesion, tumor progression, and neurodegenerative disorders. 32 Clusterin is known to be expressed in the ocular surface epithelium, but it is significantly reduced in the keratinized conjunctiva, suggesting its potential role in maintaining the ocular surface epithelium in a non-keratinizing state. 33,34 In addition, it has been found that Clusterin strongly binds MMP-9, inhibiting its enzymatic activity and MMP-9-mediated degradation of the tight junction structures formed between human epithelial cells, thereby preventing tumor invasion.…”

Section: Discussionmentioning

confidence: 99%

Altered gene expression in conjunctival squamous cell carcinoma

et al. 2016

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Conjunctival squamous cell carcinoma is a malignancy of the ocular surface. The molecular drivers responsible for the development and progression of this disease are not well understood. We therefore compared the transcriptional profiles of eight snap-frozen conjunctival squamous cell carcinomas and one in situ lesion with normal conjunctival specimens in order to identify diagnostic markers or therapeutic targets. RNA was analyzed using oligonucleotide microarrays, and a wide range of transcripts with altered expression identified, including many dysregulated in carcinomas arising at other sites. Among the upregulated genes, we observed more than 30-fold induction of the matrix metalloproteinases, MMP-9 and MMP-11, as well as a prominent increase in the mRNA level of a calcium-binding protein important for the intracellular calcium signaling, S100A2, which was induced over 20-fold in the tumor cohort. Clusterin was the most downregulated gene, with an approximately 180-fold reduction in the mRNA expression. These alterations were all confirmed by qPCR in the samples used for initial microarray analysis. In addition, immunohistochemical analysis confirmed the overexpression of MMP-11 and S100A2, as well as reductions in clusterin, in several independent in situ carcinomas of conjunctiva. These data identify a number of alterations, including upregulation of MMP-9, MMP-11, and S100A2, as well as downregulation of clusterin, associated with epithelial tumorigenesis in the ocular surface.

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“…To the best of our knowledge, they have distinct biological functions, e.g. sCLU reportedly can prevent cell death while nuclear can promote cell death (Kim et al 2012;Koltai 2014). To clarify the function of sCLU, we utilized intraventricular infusion of exogenous human ApoJ protein following CCI in mice.…”

Section: Discussionmentioning

confidence: 99%

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

Huang

Cheng

Jiang

et al. 2016

Journal of Neurochemistry

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Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in youth, but to date, effective therapies are still lacking. Previous studies revealed a marked response of apolipoprotein J (ApoJ) expression to the brain injury. The aim of this study was to determine the potential roles of ApoJ in functional recovery following TBI. After controlled cortex impact (CCI), a TBI model, in adult wild-type mice, ApoJ expression was up-regulated since 6 h post-injury and sustained for 5 days. Animals infused with recombinant human ApoJ intraventricularly at 30 min prior to CCI showed significantly reduced oxidative stress (3-nitrotyrosine, 4-hydroxynonenal) and complement activation (C5b-9). In addition, ApoJ treatment was shown to suppress the inflammatory response (glial activation, cytokine expression), blood-brain barrier disruption (Evans blue extravasation), and cerebral edema (water content) induced by CCI. Concomitantly, improved neuronal maintenance and neurological behavioral performance were observed in ApoJtreated mice compared with the vehicle group. These findings support a neuroprotective role of ApoJ via multifunctional pathways, providing a novel and encouraging treatment strategy for TBI.

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Clusterin: a key player in cancer chemoresistance and its inhibition

Cited by 139 publications

References 65 publications

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Altered gene expression in conjunctival squamous cell carcinoma

Intraventricular apolipoprotein ApoJ infusion acts protectively in Traumatic Brain Injury

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