The Wnt regulator SFRP4 inhibits mesothelioma cell proliferation, migration, and antagonizes Wnt3a via its netrin-like domain

Our plain-English summary of The Wnt regulator SFRP4 inhibits mesothelioma cell proliferation, migration, and antagonizes Wnt3a via its netrin-like domain, by V. Perumal, A.M. Dharmarajan, S.A. Fox (International Journal of Oncology, 2017).

The study

• Authors: V. Perumal, A.M. Dharmarajan, S.A. Fox
• Journal: International Journal of Oncology
• Published: 2017;51(1):362-368
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Secreted frizzled related proteins (SFRPs) are a family of Wnt regulators which are frequently downregulated in cancers. In malignant mesothelioma (MM), downregulation of SFRP4 has been reported as a mechanism which contributes to aberrant activation of oncogenic Wnt signaling. Here we investigated the biological consequences of SFRP4 in two mesothelioma cell models where this protein is downregulated. We used recombinant SFRP4 and transient overexpression to study changes in proliferation, migration and downstream signaling. We found that recombinant SFRP4 inhibited both proliferation and migration of MM cells as well as abrogating the stimulatory effect of recombinant Wnt3a. Morphologically SFRP4 induced a cytotoxic effect distinct from apoptosis and consistent with mitotic catastrophe. Overexpression of SFRP4 in these cell lines displayed similar effects as endogenous protein on cell viability, migration and nuclear morphology. We also used expression constructs to examine the role of the SFRP4 cysteine rich domain (CRD) and a netrin-like domain (NLD) in these effects. Interestingly, we found it was the NLD which mediated the biological effects of SFRP4 in these cells. Our results indicate that SFRP4 inhibits mesothelioma proliferation, migration and activates alternative cell death pathways. The finding that the NLD is responsible for these has broader implications for this protein family. Overall this study suggests that the Wnt pathway may prove a promising target for therapy in mesothelioma.

In plain English

This laboratory study tested SFRP4 on two human malignant mesothelioma cell lines, JU77 and ONE58. SFRP4 is a protein that regulates the Wnt signaling pathway and is reduced in mesothelioma. The cell lines came from fluid around the lungs of patients with malignant pleural mesothelioma. Asbestos was not studied, and no patients were treated. The authors added purified SFRP4 to the cells, or made the cells produce SFRP4 or one of its two parts, the cysteine rich domain or the netrin-like domain. Added SFRP4 reduced cell viability in a dose-dependent way in both cell lines. It also slowed cell migration in a scratch-wound test. A related protein, Wnt3a, blocked SFRP4's effect on proliferation. SFRP4 made both cell lines more sensitive to the chemotherapy drug cisplatin. The cells showed no signs of apoptosis (a common form of cell death). Instead, their nuclei showed changes characteristic of mitotic catastrophe, a different form of cell death. Producing SFRP4 or its netrin-like domain had similar effects, while the cysteine rich domain had little effect. The authors concluded that the data support targeting the Wnt pathway in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) cell culture experiments
• Who was studied: Two human malignant mesothelioma cell lines, JU77 and ONE58, originally derived from pleural effusions of different patients with malignant pleural mesothelioma
• Exposure: No asbestos exposure was studied. Cells were treated with recombinant SFRP4 and/or recombinant Wnt3a (mostly 250 pg/ml) and with cisplatin, or were transfected with constructs expressing full-length SFRP4, its cysteine rich domain (CRD) or its netrin-like domain (NLD)
• Main results:
  • In both cell lines, recombinant SFRP4 caused dose-dependent inhibition of cell viability/proliferation
  • In both cell lines, 250 pg/ml SFRP4 significantly inhibited proliferation, and 250 pg/ml Wnt3a blocked this effect
  • Wnt3a on its own appeared to raise proliferation at 250 pg/ml and lower it at higher concentrations, but these effects were not statistically significant
  • SFRP4 appeared to sensitize both cell lines to cisplatin, with a statistically significant difference in IC50 values (p=0.0233 for JU77 and p=0.0046 for ONE58)
  • SFRP4 significantly inhibited wound closure (cell migration) in both cell lines. Wnt3a had little effect on its own but significantly reduced the effect of SFRP4 in JU77 cells
  • SFRP4 did not significantly activate caspase-3. Apoptotic nuclei were not seen. Nuclear changes characteristic of mitotic catastrophe were seen in both cell lines
  • SFRP4 downregulated beta-catenin and Dvl-3 in JU77, but these effects were not seen in ONE58
  • In both cell lines, overexpression of SFRP4 and of the NLD significantly reduced proliferation/viability, while the CRD had little effect
  • Overexpression of SFRP4 and of the NLD significantly inhibited wound closure; the CRD had no effect
• The authors' conclusion: The authors concluded that SFRP4, when reintroduced into mesothelioma cells, inhibits proliferation and migration and induces nuclear changes characteristic of mitotic catastrophe. In their view these effects are mainly due to the netrin-like domain, and the data support targeting the Wnt pathway in mesothelioma

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Apoptosis.

Related studies

• PIM1 knockdown inhibits cell proliferation and invasion of mesothelioma cells — A.S. Mawas, V.J. Amatya, et al. (2017)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)
• Overexpression or absence of calretinin in mouse primary mesothelial cells inversely affects proliferation and cell migration — W. Blum, L. Pecze, et al. (2015)
• Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth — D.A. Altomare, H. You, et al. (2005)
• Delivery of expression constructs of secreted frizzled-related protein 4 and its domains by chitosan-dextran sulfate nanoparticles enhances their expression and anti-cancer effects — V. Perumal, F. Arfuso, et al. (2018)
• AHNAK is highly expressed and plays a key role in cell migration and invasion in mesothelioma — H. Sudo, A.B. Tsuji, et al. (2014)

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