Alkyl-lysophospholipids activate the SAPK/JNK signaling pathway and enhance radiation-induced apoptosis

Ruiter, G.A.; Zerp, S.F.; Bartelink, Harry; Blitterswijk, Wim J. van; Verheij, Marcel

doi:10.1016/s0959-8049(99)81109-5

Cited by 77 publications

(106 citation statements)

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“…Previous studies have shown a critical role for persistent JNK activation in EDLF-mediated apoptosis (Gajate et al, 1998;Ruiter et al, 1999), EDLF being a rapid and potent JNK activator (Gajate et al, 1998;Ruiter et al, 1999) as well as a strong inducer of c-jun upregulation in leukemic cells (Mollinedo et al, 1994).…”

Section: Apoptosis Chaperoning Role Of Hsp90 In Lipid Rafts T Nieto-mmentioning

confidence: 99%

“…Because Hsp90 and JNK were recruited in lipid rafts, and EDLF-induced apoptosis is dependent on sustained JNK activation (Gajate et al, 1998;Ruiter et al, 1999), we hypothesized that Hsp90 might interact with unusual client proteins when present in a new scenario, favoring apoptosis and JNK activation. Persistent JNK activation is associated with apoptosis, whereas transient JNK activation is linked to proliferating and differentiating responses (Chen et al, 1996).…”

Section: Hsp90 Interacts With Jnk Upon Their Recruitment Into Lipid Rmentioning

confidence: 99%

“…This has led to the notion that Fas/CD95 concentration in lipid rafts is a novel mode of action for anti-cancer drugs and a potential target in cancer chemotherapy . In addition, EDLF-induced apoptosis is mediated by c-Jun N-terminal kinase (JNK) persistent activation (Gajate et al, 1998;Ruiter et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Apoptosis Chaperoning Role Of Hsp90 In Lipid Rafts T Nieto-mmentioning

confidence: 99%

Section: Hsp90 Interacts With Jnk Upon Their Recruitment Into Lipid Rmentioning

confidence: 99%

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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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“…This efficacy has been proven in vitro and in preclinical mouse models (11)(12)(13). Synthetic phospholipids such as alkyllysophospholipids have also been shown to act as radiosensitizers and to enhance radiation-induced apoptosis in vitro (14)(15)(16). The PKC inhibitor, PKC412, has also been shown to increase the apoptotic sensitivity of cancer cells through the inhibition of the PI3K/Akt signaling pathway (17).…”

Section: Discussionmentioning

confidence: 99%

“…TRAIL (11)(12)(13), synthetic phospholipids such as alkyllysophospholipids (14)(15)(16), the PKC inhibitor, PKC412 (17), other drugs such as Cox-2 inhibitors, betulinic acid, and proteasome inhibitors have all been suggested as radiosensitizers (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells

Yee

Song²,

Jeong³

et al. 2007

Oncol Rep

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Submicromolar doses of alkyl‐lysophospholipids induce rapid internalization, but not activation, of epidermal growth factor receptor and concomitant MAPK/ERK activation in A431 cells

Ruiter

Verheij

Zerp

et al. 2002

Intl Journal of Cancer

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Synthetic ALPs, e.g., Et-18-OCH 3 and HePC, are anticancer agents that accumulate in cell membranes, where they interfere with lipid-mediated signal transduction. We previously reported that ALPs, when added at micromolar concentrations (5-25 M), inhibit growth factor-induced MAPK/ ERK activation and enhance radiation-induced apoptosis. We now show that, at nanomolar doses (10 -500 nM), ALPs activate the MAPK/ERK pathway in A431 cells without stimulating cell proliferation. Strikingly, ALPs (500 nM) also trigger rapid clustering and internalization of the EGFR in A431 cells. Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, blocks ALP-induced MAPK/ERK activation but not EGFR internalization. We found no evidence for ALPs acting via G protein-coupled receptors and/or transactivation of EGFRs, as determined by calcium mobilization, EGFR phosphorylation and Grb2 binding assays. Since ALPs readily intercalate into the plasma membrane, our data suggest that they induce subtle changes in the lipid microenvironment of the EGFR, resulting in clustering and internalization of the EGFR and concomitant MAPK/ERK activation.

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Alkyl-lysophospholipids activate the SAPK/JNK signaling pathway and enhance radiation-induced apoptosis

Cited by 77 publications

References 0 publications

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

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

A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells

Submicromolar doses of alkyl‐lysophospholipids induce rapid internalization, but not activation, of epidermal growth factor receptor and concomitant MAPK/ERK activation in A431 cells

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