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SPARC regulates transforming growth factor beta induced (TGFBI) extracellular matrix deposition and paclitaxel response in ovarian cancer cells

SPARC regulates transforming growth factor beta induced (TGFBI) extracellular matrix deposition and paclitaxel response in ovarian cancer cells
SPARC regulates transforming growth factor beta induced (TGFBI) extracellular matrix deposition and paclitaxel response in ovarian cancer cells
TGFBI has been shown to sensitize ovarian cancer cells to the cytotoxic effects of paclitaxel via an integrin receptor-mediated mechanism that modulates microtubule stability. Herein, we determine that TGFBI localizes within organized fibrillar structures in mesothelial-derived ECM. We determined that suppression of SPARC expression by shRNA decreased the deposition of TGFBI in mesothelial-derived ECM, without affecting its overall protein expression or secretion. Conversely, overexpression of SPARC increased TGFBI deposition. A SPARC-YFP fusion construct expressed by the Met5a cell line co-localized with TGFBI in the cell-derived ECM. Interestingly, in vitro produced SPARC was capable of precipitating TGFBI from cell lysates dependent on an intact SPARC carboxy-terminus with in vitro binding assays verifying a direct interaction. The last 37 amino acids of SPARC were shown to be required for the TGFBI interaction while expression of a SPARC-YFP construct lacking this region (aa 1–256) did not interact and co-localize with TGFBI in the ECM. Furthermore, ovarian cancer cells have a reduced motility and decreased response to the chemotherapeutic agent paclitaxel when plated on ECM derived from mesothelial cells lacking SPARC compared to control mesothelial-derived ECM. In conclusion, SPARC regulates the fibrillar ECM deposition of TGFBI through a novel interaction, subsequently influencing cancer cell behavior.
1932-6203
1-20
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Brenton, James D.
834c3a0f-a453-4de5-908d-c5c21f1533af
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Andrews, Melissa
ae987a2f-878e-4ae3-a7a3-a7170712096c
Brenton, James D.
834c3a0f-a453-4de5-908d-c5c21f1533af

Tumbarello, David A., Andrews, Melissa and Brenton, James D. (2016) SPARC regulates transforming growth factor beta induced (TGFBI) extracellular matrix deposition and paclitaxel response in ovarian cancer cells. PLoS ONE, 11 (9), 1-20. (doi:10.1371/journal.pone.0162698). (PMID:27622658)

Record type: Article

Abstract

TGFBI has been shown to sensitize ovarian cancer cells to the cytotoxic effects of paclitaxel via an integrin receptor-mediated mechanism that modulates microtubule stability. Herein, we determine that TGFBI localizes within organized fibrillar structures in mesothelial-derived ECM. We determined that suppression of SPARC expression by shRNA decreased the deposition of TGFBI in mesothelial-derived ECM, without affecting its overall protein expression or secretion. Conversely, overexpression of SPARC increased TGFBI deposition. A SPARC-YFP fusion construct expressed by the Met5a cell line co-localized with TGFBI in the cell-derived ECM. Interestingly, in vitro produced SPARC was capable of precipitating TGFBI from cell lysates dependent on an intact SPARC carboxy-terminus with in vitro binding assays verifying a direct interaction. The last 37 amino acids of SPARC were shown to be required for the TGFBI interaction while expression of a SPARC-YFP construct lacking this region (aa 1–256) did not interact and co-localize with TGFBI in the ECM. Furthermore, ovarian cancer cells have a reduced motility and decreased response to the chemotherapeutic agent paclitaxel when plated on ECM derived from mesothelial cells lacking SPARC compared to control mesothelial-derived ECM. In conclusion, SPARC regulates the fibrillar ECM deposition of TGFBI through a novel interaction, subsequently influencing cancer cell behavior.

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More information

Accepted/In Press date: 31 August 2016
e-pub ahead of print date: 13 September 2016
Published date: 13 September 2016
Organisations: Biomedicine, Centre for Biological Sciences

Identifiers

Local EPrints ID: 399860
URI: http://eprints.soton.ac.uk/id/eprint/399860
ISSN: 1932-6203
PURE UUID: e476d89f-215e-4edd-9b30-387bc8de8894
ORCID for David A. Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561
ORCID for Melissa Andrews: ORCID iD orcid.org/0000-0001-5960-5619

Catalogue record

Date deposited: 15 Sep 2016 08:42
Last modified: 03 Dec 2019 01:35

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