Human leukaemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy

LOMPARDIA S; PAPADEMETRIO D; MASCARÓ M; ALVAREZ E.; HAJOS S

GLYCOBIOLOGY

OXFORD UNIV PRESS INC

Lugar: Oxford; Año: 2013 vol. 23 p. 1463 - 1476

0959-6658

? Oxford Journals Life Sciences Glycobiology Advance Access 10.1093/glycob/cwt074 ? Human leukaemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy 1. Silvina Laura Lompardía, Daniela Laura Papademetrio, Marilina Mascaró,Elida María del Carmen Álvarez and Silvia Elvira Hajos +Author AffiliationsDepartment of Immunology, School of Pharmacy and Biochemistry, University of Buenos Aires (UBA), IDEHU-CONICET, Buenos Aires, 1113, Argentina 1. To whom correspondence should be addressed: Tel: +54 11 4964 8259; Fax: +54 11 4964 2400; Email: sil_escalada@hotmail.com (SL) / shajos@ffyb.uba.ar (SH) ? Received May 8, 2013. ? Revision received August 20, 2013. ? Accepted September 4, 2013. Abstract Hyaluronan is one of the major components of the extracellular matrix. Several solid tumours produce high levels of hyaluronan, which promotes survival and multidrug resistance. Hyaluronan oligomers can block hyaluronan effects. However, little is known about the role of hyaluronan in haematological malignancies. The aim of this work was to determine whether hyaluronan or its oligomers can modulate the proliferation of leukaemia cells as well as their effect on multidrug resistance. Receptors and signalling pathways involved were also analysed. For this purpose the human leukaemic cell lines K562 and Kv562, which are sensitive and resistant to Vincristine, respectively, were used. We demonstrated that hyaluronan induced cell proliferation in both cell lines. On K562 cells, this effect was mediated by CD44 and activation of both PI3K/Akt and MEK/ERK pathways, whereas on Kv562 cells the effect was mediated by RHAMM and PI3K/Akt activation. The inhibition of hyaluronan synthesis by 4-Methylumbelliferone decreased cell lines proliferation and sensitized Kv562 to the effect of Vincristine through Pgp inhibition, in both cases with senescence induction. Moreover, hyaluronan oligomers inhibited K562 proliferation mediated by CD44 as well as Akt and ERK downregulation. Furthermore, hyaluronan oligomers sensitized Kv562 cells to Vincristine by Pgp inhibition inducing senescence. We postulate that the synthesis of hyaluronan would promote leukaemia progression mediated by the triggering of the above mentioned proliferative signals. These findings highlight the potential use of hyaluronan oligomers and 4-Methylumbelliferone as coadjuvant for drug-resistant leukaemia. Key words ? Hyaluronan CD44 / RHAMM Senescence Drug-resistance Leukaemia ? © The Author 2013. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com