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.
Highlights
We analyzed the phosphorylation of Mammalian TOR (mTOR) that acts downstream of Akt, forming the complex mTOR complex 1 (mTORC1).10 We found that phosphorylation levels of mTOR (p-mTOR), as well as of its direct substrate 4E-BP1 (p-4E-BP1), were rapidly decreased after 3-h incubation with edelfosine (Figure 1c)
About 60–70% of spontaneous tumor cell apoptosis was reversed by Mantle cell lymphoma (MCL) coculture with HS-5 cells, but this value decreased to 25–35% in the presence of perifosine or edelfosine, suggesting that the presence of stroma did not prevent the killing of MCL patientderived cells by antitumor lipid (ATL)
We have found for the first time the presence of the PI3K/Akt signaling pathway in the lipid rafts of MCL cells, and provide evidence for the critical role of raft-mediated PI3K/Akt signaling in MCL cell survival
Summary
Mantle cell lymphoma (MCL) is a B cell-derived neoplasia that constitutes B6% of all non-Hodgkin lymphomas, and is characterized by the chromosomal translocation t(11;14)(q13;q32), leading to aberrant overexpression of cyclin D1.1,2 In addition to this initial oncogenic event, MCL may carry a high number of secondary chromosomal and molecular alterations that influence the aggressive behavior of this neoplasm and a poor survival outcome.[1,2] conventional chemotherapy induces highremission rates, relapse within a few years is common, contributing to a median survival of 5–7 years.[3]. Lipid raft-mediated PI3K/Akt route in MCL therapy M Reis-Sobreiro et al[2] induce apoptosis in tumor cells.[18,21,25,26,27,28,29] These ATLs include the of at least 80%, as assessed by flow cytometry detection of CD19 þ /CD5 þ ether lipid edelfosine Apoptosis induced by either edelfosine or perifosine was not blocked by tumor microenvironmental stimuli in MCL primary cultures and cell lines These results highlight the importance of raft-mediated PI3K/Akt targeting in MCL therapy. To evaluate mitochondrial transmembrane potential (DCm) disruption and the generation of reactive oxygen species, cells (106/ml) were incubated in phosphate-buffered saline (PBS) with 20 nM 3,30-dihexyloxacarbocyanine iodide [DiOC6(3)] (green fluorescence) (Molecular Probes, Leiden, The Netherlands) and 2 mM dihydroethidine (red fluorescence after oxidation)
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