Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis

Gajate, Consuelo; Fonteríz, Rosalba I.; Cabaner, C.; Alvarez-Noves, Granada; Alvarez-Rodríguez, Y; Modolell, Manuel; Mollinedo, Faustino

doi:10.1002/(sici)1097-0215(20000301)85:5<674::aid-ijc13>3.0.co;2-z

Cited by 135 publications

(224 citation statements)

References 17 publications

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“…Quantitation of apoptotic cells was determined by flow cytometry as the percentage of cells in the sub-G 1 region (hypodiploidy) in cell-cycle analysis as previously described (Gajate et al, 2000b).…”

Section: Apoptosis Assaymentioning

confidence: 99%

“…Synthetic alkyl-lysophospholipid analogs (ALPs) are a novel class of unnatural lipids with promising anticancer activity, including clinically relevant drugs such as miltefosine, perifosine and erucylphosphocholine, which act at the cell membrane level (Gajate and Mollinedo, 2002;Mollinedo et al, 2004). Edelfosine (1-O-octadecyl-2-O-methoxyrac-glycero-3-phosphocholine), considered to be the ALP prototype compound, has been shown to induce apoptosis in malignant cells in a rather selective way through the involvement of lipid rafts and ER (Mollinedo et al, 1997;Gajate et al, 2000bGajate et al, , 2004Gajate et al, , 2009aMollinedo, 2001, 2007;Gajate, 2006, 2010;Nieto-Miguel et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

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Section: Apoptosis Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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“…EDLF induces apoptosis more expeditiously in leukemic cells than in solid tumor cells (Nieto-Miguel et al, 2006), through the intracellular activation of the death receptor Fas/CD95 and its recruitment, independently of its natural ligand FasL/CD95L, into lipid rafts (Gajate et al, 2000bMollinedo, 2001, 2007). EDLF accumulates in lipid rafts (van der Luit et al, 2002;Gajate et al, 2004), leading to a redistribution of proteins in these membrane domains that eventually induces cell death Zaremberg et al, 2005;Gajate and Mollinedo, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…EDLF accumulates in lipid rafts (van der Luit et al, 2002;Gajate et al, 2004), leading to a redistribution of proteins in these membrane domains that eventually induces cell death Zaremberg et al, 2005;Gajate and Mollinedo, 2007). EDLF was the first agent reported to promote co-clustering of Fas/CD95 and membrane rafts leading to apoptosis (Gajate et al, 2000bGajate and Mollinedo, 2001), representing a new way of killing tumor cells by targeting lipid rafts. Additional antitumor drugs, including resveratrol (Delmas et al, 2003), cisplatin (Lacour et al, 2004), aplidin and perifosine (Gajate and Mollinedo, 2007), have been recently found to induce clustering of Fas/CD95 in lipid rafts.…”

Section: Introductionmentioning

confidence: 99%

Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

et al. 2007

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Heat shock protein 90 (Hsp90) is a survival signaling chaperone and a cancer chemotherapeutic target. However, we have found that inhibitors of Hsp90 diminished the apoptotic response induced in leukemic cells by the antitumor alkyl-lysophospholipid analog edelfosine, which acts through lipid raft reorganization. Edelfosine treatment recruited Hsp90, c-Jun N-terminal kinase (JNK) and apoptotic molecules in lipid rafts, but not the JNK regulators apoptosis signal-regulating kinase 1 (ASK1) and Daxx, or the survival signaling molecules extracellular signal-regulated kinase (ERK) and Akt. Following edelfosine treatment, Hsp90 bound to JNK in lipid rafts and Hsp90-JNK clusters were identified at the plasma membrane by immunoelectron microscopy. Hsp90 inhibition reduced JNK protein level in lipid rafts and turned proapoptotic persistent JNK activation into a transient response in edelfosine-treated cells. Decrease in edelfosine-induced JNK activation and apoptosis by Hsp90 inhibition was prevented through proteasome inhibition, suggesting that Hsp90 inhibition diminishes apoptosis by promoting JNK protein degradation. Expression of ASK1 dominant negative mutant did not affect JNK activation and apoptosis following edelfosine treatment. These data indicate that lipid raft-recruited JNK is ASK1-independent and becomes a novel Hsp90 client protein. Our results reveal a new chaperoning role of Hsp90 on JNKmediated apoptosis following its recruitment in lipid rafts.

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“…Furthermore, the identification of other potential biomarkers for perifosine efficacy in cancer patients would allow those patients most likely to respond to perifosine, either alone or in combination with other therapies, to be selected. ALP uptake is a prerequisite for triggering the intracellular events that finally cause cell death in different cellular systems, including yeasts [8,9], the protozoan parasite Leishmania donovani [10] and cancer cells [11]. Indeed, a clear correlation between ALP uptake and apoptosis induction has been reported previously [12].…”

Section: Introductionmentioning

confidence: 96%

CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells

Muñoz-Martínez

Torres

Castanys

et al. 2010

Biochemical Pharmacology

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. CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells. Biochemical Pharmacology, Elsevier, 2010, 80 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACT:Functional aminophospholipid translocases are composed of at least two proteins: an alpha subunit from the P4 subfamily of P-type ATPases and a beta subunit from the CDC50-Lem3p family. Over-expression and knockdown of the human beta subunit CDC50A in KB cells enhanced and decreased, respectively, the uptake of both fluorescent aminophospholipid analogues and the anticancer alkylphospholipid perifosine. Confocal microscopy showed that CDC50A-V5 was localized at the endoplasmic reticulum and the Golgi complex of both KB (perifosinesensitive) and KB PER-R (perifosine-resistant, alkyl-phospholipid uptake deficient)cells, but was only widely distributed in the early and late endosomes in KB cells.Biotinylation of cell surface proteins allowed CDC50A-V5 to be detected in the plasma membrane of KB cells but not in KB PER-R cells, thereby suggesting a defect in CDC50A trafficking that could explain the inability of KB PER-R to uptake perifosine. Over-expression of CDC50A in HeLa and HEK293T cells did not increase uptake, since the protein was retained at the endoplasmic reticulum and Golgi.However, when CDC50A was co-expressed with the P4-ATPase Atp8b1, the two proteins co-localized at the plasma membrane and the uptake of aminophospholipids and perifosine increased strikingly in both cell lines. These findings suggest that CDC50A plays a key role in perifosine uptake in human cells, presumably by forming a functional plasma membrane translocator in combination with a P4-ATPase.

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Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis

Cited by 135 publications

References 17 publications

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy

CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells

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