Hyaluronan oligosaccharides induce cell death through PI3-K/Akt pathway independently of NF-kappaB transcription factor.
Several studies indicate that hyaluronan oligosaccharides (oHA) are able to modulate growth and cell survival in solid tumors; however, no studies have been undertaken to analyze the effect of oHA on T-lymphoid disorders. In this work we showed that oHA were able to induce apoptosis in lymphoma cell lines. Since PI3-K/Akt and nuclear factor-kappaB (NF-kappaB) are major factors involved in cell survival and anti-apoptotic pathways in lymphoma cells, we hypothesized that oHA could induce apoptosis through inhibition of these pathways. oHA were identified by a method which allows characterization of length using a high pH anion exchange chromatography with pulse amperometric detection (HPAEC-PAD). oHA inhibited PIP(3) production (principal product of PI3-K activity) and reduced Akt phosphorylation levels, similarly to the specific inhibitor wortmannin. However, treatment with either oHA or wortmannin failed to inhibit constitutive NF-kappaB activity and modulate IkappaBalpha protein levels, suggesting that PI3-K and NF-kappaB signaling pathways are not related in the cell lines used. Cell behavior differed using native hyaluronan (HA), which induced PIP(3) production, Akt phosphorylation, and NF-kappaB activation, although not related with cell survival since treatment with native HA showed no effect on apoptosis. Our results suggest that oHA induce apoptosis by suppression of PI3-K/Akt cell survival pathway without involving NF-kappaB activation, through a mechanism that differs from the one mediated by native HA.
Alaniz
Laura
L
Cátedra de Immunologia-IDEHU, Facultad de Farmacia y Bioquímica, Universidad de Buenires, Argentina. laualaaniz@ffyb.uba.ar
García
Mariana G
MG
Gallo-Rodriguez
Carola
C
Agusti
Rosalía
R
Sterín-Speziale
Norma
N
Hajos
Silvia E
SE
Alvarez
Elida
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D016328:NF-kappa B; D006820:Hyaluronic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt