Anti-tumour effects of all-trans retinoid acid on serous ovarian cancer

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Abstract

Background

Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. The aim of this study was to investigate the potential utility of all-trans retinoid acid (ATRA), an inhibitor of the annexin A2-S100A10 signalling pathway, as a new therapeutic against serous ovarian cancer.

Methods

In this study we determined the effects of ATRA treatment (1-5 μM) on annexin A2 and S100A10 expression, plasmin activation, and the ability of ATRA to inhibit serous ovarian cancer cell survival, motility and invasion in vitro. We also employed an ex vivo tissue explant assay to assess response to ATRA treatment in serous ovarian cancers. Cryopreserved serous ovarian cancer tissues were cultured on gelatin sponges for 72 h with ATRA (1 μM). Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively.

Results

Survival of serous ovarian cancer cells (OVCAR-3, OV-90, & OAW28) was significantly decreased by ATRA treatment (1-5 μM). ATRA (1 μM) also significantly decreased proliferation (Ki67 positivity, p = 0.0034), S100A10 protein levels ( p = 0.0273), and increased cell apoptosis (cleaved caspase-3 positivity, p = 0.0024) in serous ovarian cancer tissues using the ex vivo tissue explant assay. In OAW28 cells, reduced cell survival following ATRA treatment was associated with a reduction of S100A10 mRNA and protein levels, S100A10 and annexin A2 membrane localization, plasmin generation, motility and invasion. In contrast, ATRA inhibited OV-90 cell survival and invasion but did not affect plasmin activation or S100A10 and annexin A2 expression or membrane localization.

Conclusions

These findings suggest that ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms. Our results show that ATRA has promising potential as a novel therapy against serous ovarian cancer that warrants further evaluation.

Electronic supplementary material

The online version of this article (10.1186/s13046-018-1017-7) contains supplementary material, which is available to authorized users.

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Most cited references 39

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Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors.

Thaddeus Schug, Daniel C Berry, Natacha S. Shaw … (2007)

Transcriptional activation of the nuclear receptor RAR by retinoic acid (RA) often leads to inhibition of cell growth. However, in some tissues, RA promotes cell survival and hyperplasia, activities that are unlikely to be mediated by RAR. Here, we show that, in addition to functioning through RAR, RA activates the "orphan" nuclear receptor PPARbeta/delta, which, in turn, induces the expression of prosurvival genes. Partitioning of RA between the two receptors is regulated by the intracellular lipid binding proteins CRABP-II and FABP5. These proteins specifically deliver RA from the cytosol to nuclear RAR and PPARbeta/delta, respectively, thereby selectively enhancing the transcriptional activity of their cognate receptors. Consequently, RA functions through RAR and is a proapoptotic agent in cells with high CRABP-II/FABP5 ratio, but it signals through PPARbeta/delta and promotes survival in cells that highly express FABP5. Opposing effects of RA on cell growth thus emanate from alternate activation of two different nuclear receptors.

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Retinoids, retinoic acid receptors, and cancer.

Xiao-Han Tang, Lorraine Gudas (2011)

Retinoids (i.e., vitamin A, all-trans retinoic acid, and related signaling molecules) induce the differentiation of various types of stem cells. Nuclear retinoic acid receptors mediate most but not all of the effects of retinoids. Retinoid signaling is often compromised early in carcinogenesis, which suggests that a reduction in retinoid signaling may be required for tumor development. Retinoids interact with other signaling pathways, including estrogen signaling in breast cancer. Retinoids are used to treat cancer, in part because of their ability to induce differentiation and arrest proliferation. Delivery of retinoids to patients is challenging because of the rapid metabolism of some retinoids and because epigenetic changes can render cells retinoid resistant. Successful cancer therapy with retinoids is likely to require combination therapy with drugs that regulate the epigenome, such as DNA methyltransferase and histone deacetylase inhibitors, as well as classical chemotherapeutic agents. Thus, retinoid research benefits both cancer prevention and cancer treatment.

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Retinoic acid receptors: from molecular mechanisms to cancer therapy.

Alessandra di Masi, Loris Leboffe, Elisabetta De Marinis … (2015)

Retinoic acid (RA), the major bioactive metabolite of retinol or vitamin A, induces a spectrum of pleiotropic effects in cell growth and differentiation that are relevant for embryonic development and adult physiology. The RA activity is mediated primarily by members of the retinoic acid receptor (RAR) subfamily, namely RARα, RARβ and RARγ, which belong to the nuclear receptor (NR) superfamily of transcription factors. RARs form heterodimers with members of the retinoid X receptor (RXR) subfamily and act as ligand-regulated transcription factors through binding specific RA response elements (RAREs) located in target genes promoters. RARs also have non-genomic effects and activate kinase signaling pathways, which fine-tune the transcription of the RA target genes. The disruption of RA signaling pathways is thought to underlie the etiology of a number of hematological and non-hematological malignancies, including leukemias, skin cancer, head/neck cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, pancreatic cancer, liver cancer, glioblastoma and neuroblastoma. Of note, RA and its derivatives (retinoids) are employed as potential chemotherapeutic or chemopreventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. In humans, retinoids reverse premalignant epithelial lesions, induce the differentiation of myeloid normal and leukemic cells, and prevent lung, liver, and breast cancer. Here, we provide an overview of the biochemical and molecular mechanisms that regulate the RA and retinoid signaling pathways. Moreover, mechanisms through which deregulation of RA signaling pathways ultimately impact on cancer are examined. Finally, the therapeutic effects of retinoids are reported.

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Author and article information

Contributors

Noor A. Lokman: noor.lokman@adelaide.edu.au

Rachel Ho: rachelho.mt@gmail.com

Kavyadharshini Gunasegaran: dharshini_kavya67@hotmail.com

Wendy M. Bonner: wendy.bonner@adelaide.edu.au

Martin K. Oehler: martin.oehler@adelaide.edu.au

Carmela Ricciardelli:

ORCID: http://orcid.org/0000-0001-7415-1854

carmela.ricciardelli@adelaide.edu.au

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 8 January 2019

Publication date PMC-release: 8 January 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 10

Affiliations

[1 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, Discipline of Obstetrics and Gynaecology, Adelaide Medical School, , Robinson Research Institute, University of Adelaide, ; Adelaide, South Australia 5000 Australia

[2 ]ISNI 0000 0004 0367 1221, GRID grid.416075.1, Department of Gynaecological Oncology, , Royal Adelaide Hospital, ; Adelaide, South Australia 5005 Australia

Author information

Carmela Ricciardelli http://orcid.org/0000-0001-7415-1854

Article

Publisher ID: 1017

DOI: 10.1186/s13046-018-1017-7

PMC ID: 6325857

PubMed ID: 30621740

SO-VID: dd6040f8-bab1-46c8-8d87-c3425d402354

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 August 2018

Date accepted : 19 December 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000950, Cancer Council South Australia;

Award ID: N/A

Award Recipient : Carmela Ricciardelli

Funded by: FundRef http://dx.doi.org/10.13039/100009845, Ovarian Cancer Research Foundation;

Award ID: N/A

Award Recipient : Martin K. Oehler

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: serous ovarian cancer,annexin a2,s100a10,all- trans retinoic acid

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: serous ovarian cancer, annexin a2, s100a10, all- trans retinoic acid

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Anti-tumour effects of all-trans retinoid acid on serous ovarian cancer

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 39

Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors.

Retinoids, retinoic acid receptors, and cancer.

Retinoic acid receptors: from molecular mechanisms to cancer therapy.

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Cited by 16

Most referenced authors 641