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

Oncogene volume 22, pages 1431–1444 (2003)Cite this article

Abstract

p53 is the most frequently altered gene in human cancer and therefore represents an ideal target for cancer therapy. Several amino terminal p53-derived synthetic peptides were tested for their antiproliferative effects on breast cancer cell lines MDA-MB-468 (mutant p53), MCF-7 (overexpressed wild-type p53), and MDA-MB-157 (null p53). p53(15)Ant peptide representing the majority of the mouse double minute clone 2 binding site on p53 (amino acids 12–26) fused to the Drosophila carrier protein Antennapedia was the most effective. p53(15)Ant peptide induced rapid, nonapoptotic cell death resembling necrosis in all breast cancer cells; however, minimal cytotoxicity was observed in the nonmalignant breast epithelial cells MCF-10–2A and MCF-10F. Bioinformatic/biophysical analysis utilizing hydrophobic moment and secondary structure predictions as well as circular dichroism spectroscopy revealed an α-helical hydrophobic peptide structure with membrane disruptive potential. Based on these findings, p53(15)Ant peptide may be a novel peptide cancer therapeutic because it induces necrotic cell death and not apoptosis, which is uncommon in traditional cancer therapy.

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Abbreviations

CFU-GEMM:

Colony forming units for granulocytes, erythryocytes, monocytes, and macrophages

DMSO:

Dimethylsulfoxide

MTT:

3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide

PI:

Propidium iodide

CPP32:

32 kDa cysteine protease

LDH:

Lactate dehydrogenase

SDS–PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

MDM2:

Mouse double min clone 2

PARP:

Poly (ADP-ribose) polymerase

TEM:

Transmission electron microscopy

PBS:

Phosphate-buffered saline

CD:

Circular dichroism spectroscopy

BAF:

BOC-Asp(OMe)-FMK caspase inhibitor

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Acknowledgements

This work was supported in part by the National Institutes of Health RO1 Grant OH 04192 and Environmental Protection Agency Grant R826685 (to PWB-R); NIH RO1 Grant CA 82528 and a Herbert Irving Scholar Award (to RLF); and NIH RO1 Grant CA 42500, a Veteran's Affairs Merit Review Grant, and a grant from the Lustgarten Foundation for Pancreatic Cancer Research (to MRP). We thank Dr Yin Li for helpful discussion.

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Authors and Affiliations

  1. Division of Medical Oncology, Experimental Therapeutics Program, College of Physicians and Surgeons of Columbia University, New York, 10032, NY, USA

    Tamara N Do, Ramon V Rosal, Lisa Drew, Anthony J Raffo, Daniel P Petrylak & Robert L Fine

  2. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, 10032, NY, USA

    Tamara N Do, Ramon V Rosal & Paul W Brandt-Rauf

  3. Department of Pathology and Laboratory Medicine, Harbor VA Medical Center, Brooklyn, 11209, NY

    Josef Michl, Matthew R Pincus, Nicholas Cassai, Joseph Szmulewicz & Gurdip Sidhu

  4. Manhattan, 10010, NY, USA

    Josef Michl, Matthew R Pincus, Nicholas Cassai, Joseph Szmulewicz & Gurdip Sidhu

  5. Department of Pathology, SUNY Downstate Medical Center, Brooklyn, 11203, NY, USA

    Josef Michl, Matthew R Pincus, Nicholas Cassai, Joseph Szmulewicz & Gurdip Sidhu

  6. Laboratory of Metabolism, National Institutes of Health, Bethesda, 20892, MD, USA

    Fred K Friedman

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Correspondence to Robert L Fine or Paul W Brandt-Rauf.

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Do, T., Rosal, R., Drew, L. et al. Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site. Oncogene 22, 1431–1444 (2003). https://doi.org/10.1038/sj.onc.1206258

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