Authors

M. W. Lee; R. Bassiouni; N. A. Sparrow; A. Iketani; R. J. Boohaker; C. Moskowitz; P. Vishnubhotla; A. S. Khaled; J. Oyer; A. Copik; C. Fernandez-Valle; J. M. Perez;A. R. Khaled

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Abbreviated Journal Title

Cell Death Dis.

Keywords

metabolism; cancer therapy; fission/fusion; actin; nanoparticles; THERAPEUTIC PEPTIDES; CARBOXYL-TERMINUS; PORE FORMATION; BAX PROTEIN; FUSION; DYNAMICS; TARGET; DYSFUNCTION; INHIBITION; EXPRESSION; Cell Biology

Abstract

Metastasis accounts for most deaths from breast cancer, driving the need for new therapeutics that can impede disease progression. Rationally designed peptides that take advantage of cancer-specific differences in cellular physiology are an emerging technology that offer promise as a treatment for metastatic breast cancer. We developed CT20p, a hydrophobic peptide based on the C terminus of Bax that exhibits similarities with antimicrobial peptides, and previously reported that CT20p has unique cytotoxic actions independent of full-length Bax. In this study, we identified the intracellular actions of CT20p which precede cancer cell-specific detachment and death. Previously, we found that CT20p migrated in the heavy membrane fractions of cancer cell lysates. Here, using MDA-MB-231 breast cancer cells, we demonstrated that CT20p localizes to the mitochondria, leading to fusion-like aggregation and mitochondrial membrane hyperpolarization. As a result, the distribution and movement of mitochondria in CT20p-treated MDA-MB-231 cells was markedly impaired, particularly in cell protrusions. In contrast, CT20p did not associate with the mitochondria of normal breast epithelial MCF-10A cells, causing little change in the mitochondrial membrane potential, morphology or localization. In MDA-MB-231 cells, CT20p triggered cell detachment that was preceded by decreased levels of alpha 5 beta 1 integrins and reduced F-actin polymerization. Using folate-targeted nanoparticles to encapsulate and deliver CT20p to murine tumors, we achieved significant tumor regression within days of peptide treatment. These results suggest that CT20p has application in the treatment of metastatic disease as a cancer-specific therapeutic peptide that perturbs mitochondrial morphology and movement ultimately culminating in disruption of the actin cytoskeleton, cell detachment, and loss of cell viability.

Journal Title

Cell Death & Disease

Volume

5

Publication Date

1-1-2014

Document Type

Article

Language

English

First Page

11

WOS Identifier

WOS:000337229300049

ISSN

2041-4889

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