Universität zu Köln

Sievers, Elisabeth, Trautmann, Marcel ORCID: 0000-0002-5842-1196, Kindler, Dagmar, Huss, Sebastian, Gruenewald, Inga, Dirksen, Uta, Renner, Marcus, Mechtersheimer, Gunhild, Pedeutour, Florence, Aman, Pierre, Nishio, Jun, Schildhaus, Hans-Ulrich, Kirfel, Jutta, Schirmacher, Peter, Wardelmann, Eva, Buettner, Reinhard and Hartmann, Wolfgang ORCID: 0000-0002-7609-5021 (2015). SRC inhibition represents a potential therapeutic strategy in liposarcoma. Int. J. Cancer, 137 (11). S. 2578 - 2589. HOBOKEN: WILEY. ISSN 1097-0215

Full text not available from this repository.

Abstract

Liposarcomas (LS) are the most common malignant mesenchymal tumors, with an overall long-term mortality rate of 60%. LS comprise three major subtypes, i.e., well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS), myxoid/round cell liposarcoma (MLS) and pleomorphic liposarcoma (PLS). Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional significance of SRC in primary human LS and in LS-derived cell lines. Immunohistochemical and Western blot analyses reveal relevant levels of activated p-(Tyr416)-SRC in LS of the different subtypes with particular activation in MLS and PLS. Dysregulation of the SRC modifiers CSK and PTP1B was excluded as major reason for the activation of the kinase. Consistent siRNA-mediated knockdown of SRC or inhibition by the SRC inhibitor Dasatinib led to decreased proliferation of LS cell lines of the different subtypes, with MLS cells reacting particularly sensitive in MTT assays. Flow cytometric analyses revealed that this effect was due to a significant decrease in mitotic activity and an induction of apoptosis. SRC inhibition by Dasatinib resulted in dephosphorylation of SRC itself, its interacting partners FAK and IGF-IR as well as its downstream target AKT. Consistent with a particular role of SRC in cell motility, Dasatinib reduced the migratory and invasive potential of MLS cells in Boyden chamber and Matrigel chamber assays. In summary, we provide evidence that SRC activation plays an important role in LS biology and therefore represents a potential therapeutic target, particularly in MLS and PLS.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sievers, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Trautmann, Marcel UNSPECIFIED orcid.org/0000-0002-5842-1196 UNSPECIFIED Kindler, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruenewald, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Dirksen, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Renner, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Mechtersheimer, Gunhild UNSPECIFIED UNSPECIFIED UNSPECIFIED Pedeutour, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Aman, Pierre UNSPECIFIED UNSPECIFIED UNSPECIFIED Nishio, Jun UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildhaus, Hans-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Schirmacher, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Wolfgang UNSPECIFIED orcid.org/0000-0002-7609-5021 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-386057
DOI:	10.1002/ijc.29645
Journal or Publication Title:	Int. J. Cancer
Volume:	137
Number:	11
Page Range:	S. 2578 - 2589
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RECEPTOR TYROSINE KINASES; MYXOID LIPOSARCOMA; DEDIFFERENTIATED LIPOSARCOMA; FAMILY KINASES; ACTIVATED SRC; PLEOMORPHIC LIPOSARCOMA; SARCOMA-CELLS; HUMAN CANCER; SOFT-TISSUE; PHASE-II Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38605