Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy
Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic r...
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doaj-ff2f0d27b1a74fbb88ae43178736e26e2020-11-25T03:40:10ZengWileyMolecular Oncology1574-78911878-02612018-06-011271077110310.1002/1878-0261.12313Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapyAnna Shteinfer‐Kuzmine0Zohar Amsalem1Tasleem Arif2Alexandra Zooravlov3Varda Shoshan‐Barmatz4Department of Life Sciences National Institute for Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelDepartment of Life Sciences National Institute for Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelDepartment of Life Sciences National Institute for Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelDepartment of Life Sciences National Institute for Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelDepartment of Life Sciences National Institute for Biotechnology in the Negev Ben‐Gurion University of the Negev Beer‐Sheva IsraelMitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic reprograming and apoptotic cell death evasion. We previously developed cell‐penetrating VDAC1‐derived peptides that interact with hexokinase (HK), Bcl‐2, and Bcl‐xL to prevent the anti‐apoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma. In this study, we demonstrated the sensitivity of a panel of genetically characterized cancer cell lines, differing in origin and carried mutations, to VDAC1‐based peptide‐induced apoptosis. Noncancerous cell lines were less affected by the peptides. Furthermore, we constructed additional VDAC1‐based peptides with the aim of improving targeting, selectivity, and cellular stability, including R‐Tf‐D‐LP4, containing the transferrin receptor internalization sequence (Tf) that allows targeting of the peptide to cancer cells, known to overexpress the transferrin receptor. The mode of action of the VDAC1‐based peptides involves HK detachment, interfering with the action of anti‐apoptotic proteins, and thus activating multiple routes leading to an impairment of cell energy and metabolism homeostasis and the induction of apoptosis. Finally, in xenograft glioblastoma, lung, and breast cancer mouse models, R‐Tf‐D‐LP4 inhibited tumor growth while inducing massive cancer cell death, including of cancer stem cells. Thus, VDAC1‐based peptides offer an innovative new conceptual framework for cancer therapy.https://doi.org/10.1002/1878-0261.12313apoptosiscancermetabolismmitochondriapeptidesVDAC1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Shteinfer‐Kuzmine Zohar Amsalem Tasleem Arif Alexandra Zooravlov Varda Shoshan‐Barmatz |
spellingShingle |
Anna Shteinfer‐Kuzmine Zohar Amsalem Tasleem Arif Alexandra Zooravlov Varda Shoshan‐Barmatz Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy Molecular Oncology apoptosis cancer metabolism mitochondria peptides VDAC1 |
author_facet |
Anna Shteinfer‐Kuzmine Zohar Amsalem Tasleem Arif Alexandra Zooravlov Varda Shoshan‐Barmatz |
author_sort |
Anna Shteinfer‐Kuzmine |
title |
Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy |
title_short |
Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy |
title_full |
Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy |
title_fullStr |
Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy |
title_full_unstemmed |
Selective induction of cancer cell death by VDAC1‐based peptides and their potential use in cancer therapy |
title_sort |
selective induction of cancer cell death by vdac1‐based peptides and their potential use in cancer therapy |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2018-06-01 |
description |
Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+, and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic reprograming and apoptotic cell death evasion. We previously developed cell‐penetrating VDAC1‐derived peptides that interact with hexokinase (HK), Bcl‐2, and Bcl‐xL to prevent the anti‐apoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma. In this study, we demonstrated the sensitivity of a panel of genetically characterized cancer cell lines, differing in origin and carried mutations, to VDAC1‐based peptide‐induced apoptosis. Noncancerous cell lines were less affected by the peptides. Furthermore, we constructed additional VDAC1‐based peptides with the aim of improving targeting, selectivity, and cellular stability, including R‐Tf‐D‐LP4, containing the transferrin receptor internalization sequence (Tf) that allows targeting of the peptide to cancer cells, known to overexpress the transferrin receptor. The mode of action of the VDAC1‐based peptides involves HK detachment, interfering with the action of anti‐apoptotic proteins, and thus activating multiple routes leading to an impairment of cell energy and metabolism homeostasis and the induction of apoptosis. Finally, in xenograft glioblastoma, lung, and breast cancer mouse models, R‐Tf‐D‐LP4 inhibited tumor growth while inducing massive cancer cell death, including of cancer stem cells. Thus, VDAC1‐based peptides offer an innovative new conceptual framework for cancer therapy. |
topic |
apoptosis cancer metabolism mitochondria peptides VDAC1 |
url |
https://doi.org/10.1002/1878-0261.12313 |
work_keys_str_mv |
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1724535770964819968 |