Hyaluronan oligosaccharides induce cell death through PI3-K/Akt pathway independently of NF-κB transcription factor

Abstract

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.

Hyaluronan Synthase 2 Protects Skin Fibroblasts against Apoptosis Induced by Environmental Stress

“…HA is reported to protect against apoptosis and to promote survival in various types of cells, including granulosa cells (44), articular chondrocytes (45,46), and human aortic smooth muscle cells (37). In contrast, other studies showed that HA treatment induces cell death in cultured human gingival fibroblasts (47) and lymphoma cell lines (48). Thus, the regulatory effect of HA upon cell viability appears to depend upon cell context, even when controlling for the size of HA, because high molecular weight HA has been shown to either promote cellular survival (37) or induce cell death (49) in different cell types.…”

Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P‐glycoprotein activity and PI3K/Akt pathway

“…Our results are in agreement with previous studies demonstrating that oHA induces apoptosis by suppressing the PI3K/Akt cell survival pathway. 15,21 This pathway appears to be critical for survival of multidrug resistant cells. Indeed, aberrantly activated PI3K/Akt pathway increases antiapoptotic signals, overwhelms proapoptotic signals of antineoplasic drugs and confers drug resistance limiting success of chemotherapy.…”

“…21 Briefly, oligosaccharides were obtained after enzymatic digestion of LMW-HA (5 mg/ml) with bovine testicular hyaluronidase (Hase) employing 500 U/mg of HA incubating at 37°C for 24 hr. The reaction was stopped by boiling for 5 min.…”

“…21 To investigate the effects of oHA and native HA on this pathway, PI3K activity was measured through the production of PIP3. As shown in Figure 2a, treatment with 300 lg/ml oHA significantly reduced PIP3 production in the 3 cell lines, comparable to inhibition levels obtained after treatment with the specific PI3K inhibitor, LY294002 (10 lM).…”

Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer

“…induce cell death in lymphoma cells 35 and inhibit anchorage-independent growth in lung, mammary, and colon cancer cell lines through PI3K/Akt pathway in vitro. 14 The treatment of HA oligos reduces tumor volume in vivo in lung and breast cancers, 14 osteosarcoma, 20 and melanoma.…”