Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site

Do, Tamara N.; Rosal, Ramon; Drew, Lisa; Raffo, Anthony J.; Michl, Josef; Pincus, Matthew R.; Friedman, Fred K.; Petrylak, Daniel P.; Cassai, Nicholas; Szmulewicz, Joseph; Sidhu, Gurdip S.; Fine, Robert L.; Brandt‐Rauf, Paul W.

doi:10.1038/sj.onc.1206258

Cited by 67 publications

(90 citation statements)

References 39 publications

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“…None of these sets of cells was induced to undergo apoptosis as revealed by the absence of enhanced caspase activity above background (Fig. S2B), consistent with our prior findings that PNC-27 induces tumor cell necrosis and not apoptosis (1)(2)(3)(4)(5). Control peptide PNC-29 (200 μg∕ml), had no effect on either LDH release or the viability of any of the four sets of transfected cells, suggesting that PNC-27 binds specifically to HDM-2 on the cell membrane, allowing for its cytotoxicity.…”

Section: Resultssupporting

confidence: 78%

“…PNC-27 does not kill MCF-10-2A cells (2). However, transfected cells that express full-length HDM-2-CVVK in their membranes become susceptible to the action of this peptide.…”

Section: Binding Of Pnc-27 To Hdm-2 In Cell Membranes Is Critical To Itsmentioning

confidence: 99%

“…We have found previously that the peptide PNC-27, containing the HDM-2-binding domain of p53, residues 12-26, attached to a transmembrane-penetrating or membrane residency peptide (MRP) on its carboxyl terminal end, and PNC-28 (p53 residues 17-26-MRP) induce tumor cell necrosis by forming pores in cancer cell membranes but have no effects on a number of untransformed cells, including human stem cells from cord blood (1)(2)(3)(4), and eradicate tumors in nude mice (5). The p53-HDM-2 complex results in the catabolism of p53 (6).…”

Section: Hdm-2 Binding | Membranolysis | Three-dimensional Structure mentioning

confidence: 99%

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Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Sarafraz-Yazdi

Bowne

Adler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.

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Section: Resultssupporting

confidence: 78%

“…PNC-27 does not kill MCF-10-2A cells (2). However, transfected cells that express full-length HDM-2-CVVK in their membranes become susceptible to the action of this peptide.…”

Section: Binding Of Pnc-27 To Hdm-2 In Cell Membranes Is Critical To Itsmentioning

confidence: 99%

Section: Hdm-2 Binding | Membranolysis | Three-dimensional Structure mentioning

confidence: 99%

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Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Sarafraz-Yazdi

Bowne

Adler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…We had shown previously that this p53 N-terminal peptide induced cell death only by necrosis without apoptosis. 36,37 …”

Section: Lactate Dehydrogenase Release Assay For Detection Of Necrosismentioning

confidence: 99%

“…As shown in Figure 3b, when compared to the maximal LDH release (MLR), early LDH release into the cytoplasm by 1 hr did not occur after exposure to 30 M p53p-Ant. The positive control for necrosis, 30 M p53(15)Ant that is a p53 N-terminal peptide (aa [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] shown by us to induce only necrosis without any evidence for apoptosis, 36,37 was carried out simultaneously. The N-terminal p53 peptide induced significant necrosis as evidenced by an early LDH release assay by 1 hr.…”

Section: P53 C-terminal Peptide-induced Cell Death: Apoptosis Vs Necmentioning

confidence: 99%

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

Mao

Rosal

et al. 2005

Intl Journal of Cancer

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A p53 C-terminal peptide (aa 361-382, p53p), fused at its Cterminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The The p53 tumor suppressor gene is one of the most commonly mutated genes found in human malignancies. 1 More than 50% of human tumors, including breast cancers, are associated with missense mutations or deletions of p53 and most of the missense mutations map to the DNA-binding domain of the protein. 2,3 p53 protein functions in the transcription of growth inhibiting genes, apoptosis, cell cycle arrest and DNA repair. 4 -6 p53 is a sequencespecific transcription factor that transactivates a number of genes whose products are involved in cell growth regulation. These include p21 (a cyclin-dependent kinase inhibitor known to arrest the cell cycle mainly in G1/S phase), GADD45 for DNA repair and Bax and Fas/APO-1 for apoptosis. 7-11 p53 induced Fas-FADD binding and transiently sensitized cells to Fas-induced apoptosis. 12 Programmed cell death depends on conserved structural moieties that transmit and regulate the death signal. This is most evident in death receptors of the tumor necrosis factor receptor (TNF-R) super-family. The intracellular regions of the Fas/CD95 and TNFR1 death receptors have a moderately well conserved NH2-region of about 80 residues that is required for death signalling and has been called the 'death domain' (DD). 13,14 Fas/CD95 induces rapid apoptosis upon binding to Fas ligand through the autocrine/paracrine signalling pathway. 15 When activated, the intracellular death domain in Fas/CD95 binds to FADD/MORT-1 at its C-terminus, which then recruits caspase-8 to FADD. A member of the TNF ligand family identified more recently is TNF-related apoptosis-inducing ligand (TRAIL). TRAIL shows high homology to Fas Ligand and binds to the TRAIL receptor family. TRAILinduced caspase activation shares many of same caspases involved in Fas/CD95 and TNF-induced cell death mechanisms. 16 FADD/ MORT-1 is a cytosolic adaptor protein, which is critical for signalling from Fas/APO-1 and other TNF-R family members. 17 Two protein interaction domains have been identified in FADD/ MORT-1. The C-terminal 'death domain' is needed for ...

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Cell‐Penetrating Peptides in Cancer Targeting

Kurrikoff

Suhorut

Langel

2011

Drug Delivery in Oncology

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Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site

Cited by 67 publications

References 39 publications

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

Cell‐Penetrating Peptides in Cancer Targeting

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