Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma

Abstract

Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment.

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…However, edelfosine has also been shown to inhibit Akt by displacing survival Akt signaling pathway from lipid rafts in mantle cell lymphoma cells (Reis-Sobreiro, et al, 2013). Taken together, current evidence suggests that edelfosine can induce cell death in cancer cells by recruiting apoptotic molecules in lipid rafts and displacing survival molecules from these membrane domains .…”

“…Perifosine blocks Akt plasma membrane localization, thus preventing its activation (Kondapaka, et al, 2003). In this regard, edelfosine and perifosine have been recently reported to displace Akt as well as regulatory proteins from lipid rafts (Reis-Sobreiro, et al, 2013). Furthermore, perifosine, as well as edelfosine, have also been…”

“…Akt signaling inhibition (Reis-Sobreiro, et al, 2013;Ruiter, et al, 2003). Edelfosine activates JNK through its recruitment into rafts (Gajate, et al, 2004;Nieto-Miguel, et al, 2008) and endoplasmic reticulum stress response (Gajate, et al, 2012;Nieto-Miguel, et al, 2007).…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Our results demonstrate that in the presence of high levels of sulfatides, the relocalization of PDGFR␣ to non-DRM domains and phosphorylation of Thr 308 and Ser 473 of AKT are severely compromised. These findings further underline the importance of DRM integrity in AKT signaling activation (70,71). Although the molecular mechanism by which sulfatides reduce the association of the receptor in DRMs is unclear, the involve- .…”

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

“…Activated ERK1/2 translocates to the nucleus and transactivates transcription factors such as Ets while Akt phosphorylates and inactivates transcription factor such as forkhead box O (FOXO1), changing gene expression to promote growth or mitosis [43,44]. In contrast to FGF-2 that mainly acts through tyrosine kinase receptor FGFR, mCRP activates endothelial cells through cholesterol-rich lipid raft microdomains, sites of phosphorylation of signaling proteins including ERK1/2 and PI3K/Akt [45,46]. In addition, a direct association of lipid rafts with γ-secretase activity has also been revealed [47].…”