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

CORDO RUSSO R; GARCÍA MG; ALANIZ LD; BLANCO G; ALVAREZ E; HAJOS S

Creta, Grecia.

Congreso; 13º Congreso Internacional de Avances en Oncología y el 11º Simposio Internacional de Medicina Molecular.; 2008

Multidrug resistance (MDR) is one of the main reasons for failure of cancer therapy. It may be mediated by overexpression of ATP-dependent efflux pumps or alterations in survival or apoptotic pathways. The PI3K/Akt signal transduction pathway plays a central role in cell survival, proliferation, angiogenesis and migration. Akt overexpression is frequently found in human malignancies associated with chemoresistance, providing a critical target for cancer intervention. MDR can be modulated by extracellular matrix components. Hyaluronan (HA) is a large glycosaminoglycan able to influence cell migration and apoptosis. In this work we analyzed the relationship between PI3K/Akt and MDR and its modulation by HA in murine lymphoma cell lines resistant to vincristine (LBR-V160) and doxorubicin (LBR-D160). PI3K/Akt activity, analyzed by PIP3 production and phosphorylated Akt (p-Akt) expression was higher in the resistant cell lines than in the sensitive one. Inhibition with wortmannin or LY294002 improved apoptosis and blocked Pgp efflux in both resistant cell lines. Treatment with HA oligosaccharides (oHA) but not with HA induced higher apoptosis levels. Besides, oHA sensitized LBR-D160 and LBR-V160 to vincristine-induced apoptosis. This effect was mediated through decreasing PI3K/Akt pathway as well as Pgp activity. We also analyzed the effect of HA on cell migration. The cell lines presented different migratory capacity, being LBR-D160 the one that showed a significant increase in HA-dependent migration. Western blot and confocal microscopy demonstrated that Tiam1 expression was higher in the resistant cell lines than in the sensitive one. Treatment with HA increased Tiam1 expression as well as PI3K/Akt while treatment with wortmannin decreased migratory capacity and down regulated Tiam1 activation. We conclude that either PI3K/Akt inhibition or oHA treatment modulate MDR by both decreasing PI3K/Akt pathway and Pgp function. Besides, HA induces migration of resistant cell lines through Tiam1 activation mediated by PI3K/Akt pathway.