Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy

Anna Shteinfer-Kuzmine, Zohar Amsalem, Tasleem Arif, Alexandra Zooravlov, Varda Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca 2+ , 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.

Original languageEnglish
Pages (from-to)1077-1103
Number of pages27
JournalMolecular Oncology
Volume12
Issue number7
DOIs
StatePublished - Jun 2018
Externally publishedYes

Keywords

  • VDAC1
  • apoptosis
  • cancer
  • metabolism
  • mitochondria
  • peptides

Fingerprint

Dive into the research topics of 'Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy'. Together they form a unique fingerprint.

Cite this