PI3K/AKT signaling pathway is modulated by Hyaluronan in lymphoma cell lines resistant to vincristine and doxorubicin.

ROSALÍA CORDO RUSSO; MARIANA GARCÍA; LAURA ALANIZ; BLANCO GUILLERMO; ELIDA ALVAREZ; SILVIA HAJOS

Hersonissos, Crete, Greece

Congreso; 13th World Congress on Advances in Oncology and 11th Int. Symposium on Molecular Medicine; 2008

Medical School University of Crete, International Journal of Oncology, Oncology Reports, International Journal of Molecular Medicine and Molecular Medicine Report

Multidrug resistance (MDR) is one of the main reasons for failure of cancer therapy. It maybe mediated by overexpression of ATP-dependent efflux pumps or alterations in survival orapoptotic pathways. The PI3K/Akt signal transduction pathway plays a central role in cellsurvival, proliferation, angiogenesis and migration. Akt overexpression is frequently foundin human malignancies associated with chemoresistance, providing a critical target forcancer intervention. MDR can be modulated by extracellular matrix components.Hyaluronan (HA) is a large glycosaminoglycan able to influence cell migration andapoptosis. In this work we analyzed the relationship between PI3K/Akt and MDR and itsmodulation by HA in murine lymphoma cell lines resistant to vincristine (LBR-V160) anddoxorubicin (LBR-D160). PI3K/Akt activity, analyzed by PIP3 production andphosphorylated Akt (p-Akt) expression was higher in the resistant cell lines than in thesensitive one. Inhibition with wortmannin or LY294002 improved apoptosis and blockedPgp efflux in both resistant cell lines. Treatment with HA oligosaccharides (oHA) but notwith HA induced higher apoptosis levels. Besides, oHA sensitized LBR-D160 and LBRV160to vincristine-induced apoptosis. This effect was mediated through decreasingPI3K/Akt pathway as well as Pgp activity. We also analyzed the effect of HA on cellmigration. The cell lines presented different migratory capacity, being LBR-D160 the onethat showed a significant increase in HA-dependent migration. Western blot and confocalmicroscopy demonstrated that Tiam1 expression was higher in the resistant cell lines thanin the sensitive one. Treatment with HA increased Tiam1 expression as well as PI3K/Aktwhile treatment with wortmannin decreased migratory capacity and down regulated Tiam1activation. We conclude that either PI3K/Akt inhibition or oHA treatment modulate MDRby both decreasing PI3K/Akt pathway and Pgp function. Besides, HA induces migration ofresistant cell lines through Tiam1 activation mediated by PI3K/Akt pathway.