TAT-RasGAP317–326-mediated tumor cell death sensitization can occur independently of Bax and Bak

The final products obtained by the oxidation of small model peptides containing the thioether function, either methionine or S-methyl cysteine, have been characterized by tandem mass spectrometry and IR Multiple Photon Dissociation (IRMPD) spectroscopy. The modified positions have been clearly identified by the CID-MS(2) fragmentation mass spectra with or without loss of sulfenic acid, as well as by the vibrational signature of the sulfoxide bond at around 1000 cm(-1). The oxidation of the thioether function did not lead to the same products in these model peptides. The sulfoxide and sulfone (to a lesser extent) have been clearly identified as final products of the oxidation of S-methyl-glutathione (GS-Me). Decarboxylation or hydrogen loss are the major oxidation pathways in GS-Me, while they have not been observed in tryptophan-methionine and methionine-tryptophan (Trp-Met and Met-Trp). Interestingly, tryptophan is oxidized in the dipeptide Met-Trp, while that is not the case in the reverse sequence (Trp-Met).

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“…10,11 Any modification in this sequence would lead to tumour growth. 10,11 Any modification in this sequence would lead to tumour growth.…”

Section: And References Therein)mentioning

confidence: 99%

Tandem mass spectrometry and infrared spectroscopy as a tool to identify peptide oxidized residues

Scuderi

Ignasiak

Serfaty

et al. 2015

Phys. Chem. Chem. Phys.

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“…Fragment N2 and fragment N2-derived peptides sensitize tumor cells to anti-cancer drugs (28, 64 -66), but the underlying mechanisms remain obscure (67,68). Here we show that fragment N2 potently inhibits FGF1-induced phosphorylation of ERK2 and Akt.…”

Section: Discussionmentioning

confidence: 67%

RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Cailliau

Lescuyer

Burnol

et al. 2015

Journal of Biological Chemistry

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Background: RasGAP and its stress-activated caspase-3-generated fragments N and N2 have the potential to regulate receptor tyrosine kinase (RTK) signaling. Results: RasGAP and fragment N favor FGF1-mediated signaling via different mechanisms, whereas fragment N2 blocks it. Conclusion: Stress, via the cleavage of RasGAP, modulates RTK signaling. Significance: This work provides a mechanistic framework of how stress impacts on cell signaling.

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“…The mechanism of action of TAT-RasGAP 317-326 remains to be precisely determined [ 18 – 20 ]. We initially assumed that working with a large panel of cell lines and cytotoxic agents would allow us to draw a pattern that could be used to predict which type of childhood tumors display sensitivity to TAT-RasGAP 317-326 in response to a given drug.…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously shown that this peptide does not favor the death of tumor cells by modulating Ras activity, MAPK signaling pathways, NF-κB transcriptional activity, Akt protein levels and phosphorylation status [ 18 , 19 ]. Moreover, the Bcl-2 family members, which regulate mitochondrial-dependent cell death, were shown to be individually dispensable for the sensitizing activity of the peptide [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Chemosensitizing Activity of TAT-RasGAP317-326 in Childhood Cancers

2015

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Although current anti-cancer protocols are reasonably effective, treatment-associated long-term side effects, induced by lack of specificity of the anti-cancer procedures, remain a challenging problem in pediatric oncology. TAT-RasGAP317-326 is a RasGAP-derived cell-permeable peptide that acts as a sensitizer to various anti-cancer treatments in adult tumor cells. In the present study, we assessed the effect of TAT-RasGAP317-326 in several childhood cancer cell lines. The RasGAP-derived peptide-induced cell death was analyzed in several neuroblastoma, Ewing sarcoma and leukemia cell lines (as well as in normal lymphocytes). Cell death was evaluated using flow cytometry methods in the absence or in the presence of the peptide in combination with various genotoxins used in the clinics (4-hydroperoxycyclophosphamide, etoposide, vincristine and doxorubicin). All tested pediatric tumors, in response to at least one genotoxin, were sensitized by TAT-RasGAP317-326. The RasGAP-derived peptide did not increase cell death of normal lymphocytes, alone or in combination with the majority of the tested chemotherapies. Consequently, TAT-RasGAP317-326 may benefit children with tumors by increasing the efficacy of anti-cancer therapies notably by allowing reductions in anti-cancer drug dosage and the associated drug-induced side effects.

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TAT-RasGAP317–326-mediated tumor cell death sensitization can occur independently of Bax and Bak

Abstract: The increase of cancer specificity and efficacy of anti-tumoral agents are prime strategies to overcome the deleterious side effects associated with anti-cancer treatments. We described earlier a cell-permeable protease-resistant peptide derived from the p120 RasGAP protein,

Cited by 10 publications

References 51 publications

Tandem mass spectrometry and infrared spectroscopy as a tool to identify peptide oxidized residues

Tandem mass spectrometry and infrared spectroscopy as a tool to identify peptide oxidized residues

RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3

Assessment of the Chemosensitizing Activity of TAT-RasGAP317-326 in Childhood Cancers

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