A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis

Ito, Shinya; Ogawa, Koji; Takeuchi, Koh; Takagi, Motoki; Yoshida, Masahito; Hirokawa, Takatsugu; Hirayama, Shoshiro; Shin‐ya, Kazuo; Shimada, Ichio; Doi, Takayuki; Goshima, Naoki; Natsume, Tohru; Nagata, Kazuhiro

doi:10.1074/jbc.m117.815936

Cited by 51 publications

(67 citation statements)

References 32 publications

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“…We have identified the Hsp47/collagen axis as a critical regulator of the cancer cell-platelet interaction. Collagen is not an ideal druggable target; however, small-molecule compounds that inhibit Hsp47-collagen interaction have been characterized recently (67). Therefore, targeting the Hsp47/collagen axis is a potential strategy to inhibit cancer cell colonization and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

Xiong

Chen

Zhang

et al. 2020

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

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102

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Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.

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Section: Discussionmentioning

confidence: 99%

Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

Xiong

Chen

Zhang

et al. 2020

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

Self Cite

102

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“…Heat shock protein 47 (HSP47) is a molecular chaperone specific to collagen and plays an important role in accumulating the collagen around fibrotic areas and it is reported to be involved in various collagen‐related disorders such as fibrosis . Therefore, HSP47 could be considered as a promising target for treatment of fibrosis .…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein 47 as indispensible participant in liver fibrosis: Possible protective effect of lactoferrin

et al. 2018

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Lactoferrin (LF) was previously suggested to have a protective effect against liver fibrosis by preventing hepatic stellate cells (HSCs) activation. The effect of LF on heat shock protein 47 (HSP47) has not yet been studied so this study was designed to investigate LF effect on HSP47 as a potential target for management of liver fibrosis and comparing it with silymarin (SM) in a thioacetamide (TAA)-induced liver fibrosis model. Rats were divided into four groups; normal control, TAA (TAA-treated), LF (LF + TAA-treated), and SM (SM + TAA-treated). After 6 weeks, both LF and SM improved the grade of cirrhosis, reduced collagen fibers deposition, inactivated HSCs, significantly decreased elevated liver enzymes, HSP47, hydroxyproline content, transforming growth factor-beta 1, matrix metalloproteinase-2, 8-hydroxydeoxyguanosine, malondialdehyde, nitric oxide levels and the percentage of alpha smooth muscle actin positive HSCs compared with TAA group. Moreover, LF significantly increased the total antioxidant capacity compared with TAA group. It could be concluded that LF is a promising antifibrotic drug and could be considered as one of the HSP47 inhibitors but SM is still more potent. © 2018 IUBMB Life, 70(8):795-805, 2018.

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“…Cells were seeded for 24 h on tissue culture plastic wells and incubated with 0.5 μM of H 47, 0.5 μM of TGF-β 1 or ascorbate for 3 h, followed by medium exchange and further culture for 24 h. The deposited collagen on the culture plate was labeled with Picro Sirius Red and quantified by spectrophotometry. Sirius red is a strong anionic dye comprising six sulfonate groups that binds preferentially to the cationic groups of the collagen fibers [51,52]. Data were normalized to the value of collagen deposition by NHDF cells without any treatment.…”

Section: Resultsmentioning

confidence: 99%

“…However, these enzymes are also involved in the hydroxylation of other matrix proteins, like Elastin or Fibronectin [73]. In contrast, the unique collagen-specificity of Hsp47, demonstrated in the literature [23,30,51], would allow up regulation of collagen deposition, without affecting any other molecule or cellular pathway.…”

Section: Discussionmentioning

confidence: 99%

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

Khan

Sankaran

Llontop

et al. 2020

BMC Mol and Cell Biol

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Background: Collagen is a structural protein that provides mechanical stability and defined architectures to skin. In collagen-based skin disorders this stability is lost, either due to mutations in collagens or in the chaperones involved in collagen assembly. This leads to chronic wounds, skin fragility, and blistering. Existing approaches to treat such conditions rely on administration of small molecules to simulate collagen production, like 4phenylbutyrate (4-PBA) or growth factors like TGF-β. However, these molecules are not specific for collagen synthesis, and result in unsolicited side effects. Hsp47 is a collagen-specific chaperone with a major role in collagen biosynthesis. Expression levels of Hsp47 correlate with collagen deposition. This article explores the stimulation of collagen deposition by exogenously supplied Hsp47 (collagen specific chaperone) to skin cells, including specific collagen subtypes quantification. Results: Here we quantify the collagen deposition level and the types of deposited collagens after Hsp47 stimulation in different in vitro cultures of cells from human skin tissue (fibroblasts NHDF, keratinocytes HaCat and endothelial cells HDMEC) and mouse fibroblasts (L929 and MEF). We find upregulated deposition of fibrillar collagen subtypes I, III and V after Hsp47 delivery. Network collagen IV deposition was enhanced in HaCat and HDMECs, while fibril-associated collagen XII was not affected by the increased intracellular Hsp47 levels. The deposition levels of fibrillar collagen were cell-dependent i.e. Hsp47-stimulated fibroblasts deposited significantly higher amount of fibrillar collagen than Hsp47-stimulated HaCat and HDMECs. Conclusions: A 3-fold enhancement of collagen deposition was observed in fibroblasts upon repeated dosage of Hsp47 within the first 6 days of culture. Our results provide fundamental understanding towards the idea of using Hsp47 as therapeutic protein to treat collagen disorders.

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A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis

Cited by 51 publications

References 32 publications

Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

Heat shock protein 47 as indispensible participant in liver fibrosis: Possible protective effect of lactoferrin

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

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