A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer

Yang Sung Sohn; Anat losub-Amir; Alfredo E. Cardenas; Ola Karmi; Merav Darash Yahana; Tal Gruman; Linda Rowland; Henri Baptiste Marjault; Lauren J. Webb; Ron Mittler; Ron Elber; Assaf Friedler; Rachel Nechushtai

doi:10.1039/d2sc01934e

A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer

Yang Sung Sohn^*, Anat losub-Amir^*, Alfredo E. Cardenas^*, Ola Karmi, Merav Darash Yahana, Tal Gruman, Linda Rowland, Henri Baptiste Marjault, Lauren J. Webb, Ron Mittler, Ron Elber, Assaf Friedler^*, Rachel Nechushtai^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-1^44-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-1^44-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.

Original language	American English
Pages (from-to)	6929-6941
Number of pages	13
Journal	Chemical Science
Volume	13
Issue number	23
DOIs	https://doi.org/10.1039/d2sc01934e
State	Published - 15 Jun 2022

Bibliographical note

Funding Information:
This research was supported by the MINERVA Center for Bio-hybrid Complex Systems at the Hebrew University and by the support of the BSF grant number 2020094 to R. N, A. F, L. J. W., and R. E. and the NIH, Grant no. GM 59796 (to R. E.) and GM 111364 (to R. E., L. J. W., R. M.); the Welch Foundation, Grant no. F-1896 (to R. E) and F-1722 (to L. J. W.); and Part of the computations were done using HPC resources from the Texas Advanced Computing Center (TACC) at the University of Texas at Austin. We gratefully acknowledge the use of facilities at the Texas Materials Institute at the University of Texas at Austin.

Publisher Copyright:
© 2022 The Royal Society of Chemistry.

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Sohn, Y. S., losub-Amir, A., Cardenas, A. E., Karmi, O., Yahana, M. D., Gruman, T., Rowland, L., Marjault, H. B., Webb, L. J., Mittler, R., Elber, R., Friedler, A., & Nechushtai, R. (2022). A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer. Chemical Science, 13(23), 6929-6941. https://doi.org/10.1039/d2sc01934e

@article{c5b3453139cc4861ab357dad0c7b07cb,

title = "A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer",

abstract = "An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-144-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-144-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.",

author = "Sohn, {Yang Sung} and Anat losub-Amir and Cardenas, {Alfredo E.} and Ola Karmi and Yahana, {Merav Darash} and Tal Gruman and Linda Rowland and Marjault, {Henri Baptiste} and Webb, {Lauren J.} and Ron Mittler and Ron Elber and Assaf Friedler and Rachel Nechushtai",

note = "Funding Information: This research was supported by the MINERVA Center for Bio-hybrid Complex Systems at the Hebrew University and by the support of the BSF grant number 2020094 to R. N, A. F, L. J. W., and R. E. and the NIH, Grant no. GM 59796 (to R. E.) and GM 111364 (to R. E., L. J. W., R. M.); the Welch Foundation, Grant no. F-1896 (to R. E) and F-1722 (to L. J. W.); and Part of the computations were done using HPC resources from the Texas Advanced Computing Center (TACC) at the University of Texas at Austin. We gratefully acknowledge the use of facilities at the Texas Materials Institute at the University of Texas at Austin. Publisher Copyright: {\textcopyright} 2022 The Royal Society of Chemistry.",

year = "2022",

month = jun,

day = "15",

doi = "10.1039/d2sc01934e",

language = "American English",

volume = "13",

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Sohn, YS, losub-Amir, A, Cardenas, AE, Karmi, O, Yahana, MD, Gruman, T, Rowland, L, Marjault, HB, Webb, LJ, Mittler, R, Elber, R, Friedler, A & Nechushtai, R 2022, 'A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer', Chemical Science, vol. 13, no. 23, pp. 6929-6941. https://doi.org/10.1039/d2sc01934e

TY - JOUR

T1 - A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells

T2 - a new approach in fighting cancer

AU - Sohn, Yang Sung

AU - losub-Amir, Anat

AU - Cardenas, Alfredo E.

AU - Karmi, Ola

AU - Yahana, Merav Darash

AU - Gruman, Tal

AU - Rowland, Linda

AU - Marjault, Henri Baptiste

AU - Webb, Lauren J.

AU - Mittler, Ron

AU - Elber, Ron

AU - Friedler, Assaf

AU - Nechushtai, Rachel

N1 - Funding Information: This research was supported by the MINERVA Center for Bio-hybrid Complex Systems at the Hebrew University and by the support of the BSF grant number 2020094 to R. N, A. F, L. J. W., and R. E. and the NIH, Grant no. GM 59796 (to R. E.) and GM 111364 (to R. E., L. J. W., R. M.); the Welch Foundation, Grant no. F-1896 (to R. E) and F-1722 (to L. J. W.); and Part of the computations were done using HPC resources from the Texas Advanced Computing Center (TACC) at the University of Texas at Austin. We gratefully acknowledge the use of facilities at the Texas Materials Institute at the University of Texas at Austin. Publisher Copyright: © 2022 The Royal Society of Chemistry.

PY - 2022/6/15

Y1 - 2022/6/15

N2 - An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-144-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-144-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.

AB - An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-144-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-144-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.

UR - http://www.scopus.com/inward/record.url?scp=85131310402&partnerID=8YFLogxK

U2 - 10.1039/d2sc01934e

DO - 10.1039/d2sc01934e

M3 - Article

C2 - 35774163

AN - SCOPUS:85131310402

SN - 2041-6520

VL - 13

SP - 6929

EP - 6941

JO - Chemical Science

JF - Chemical Science

IS - 23

ER -

A peptide-derived strategy for specifically targeting the mitochondria and ER of cancer cells: a new approach in fighting cancer

Abstract

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