A combination of a cell penetrating peptide and a protein translation inhibitor kills metastatic breast cancer cells

Linda Rowland; Henri-Baptiste Marjault; Ola Karmi; DeAna Grant; Lauren J Webb; Assaf Friedler; Rachel Nechushtai; Ron Elber; Ron Mittler

doi:10.1038/s41420-023-01627-3

A combination of a cell penetrating peptide and a protein translation inhibitor kills metastatic breast cancer cells

Cell Death Discov. 2023 Aug 31;9(1):325. doi: 10.1038/s41420-023-01627-3.

Authors

Affiliations

¹ Department of Surgery, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center University of Missouri, 1201 Rollins Street, Columbia, MO, 65201, USA.
² The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem, 9190401, Israel.
³ Electron Microscopy Core Facility, University of Missouri, 0011 NextGen Precision Health Institute, 1030 Hitt Street, Columbia, MO, 65211, USA.
⁴ Department of Chemistry, The University of Texas at Austin, 2506 Speedway STOP A5300, Austin, TX, 78712, USA.
⁵ Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem, 9190401, Israel.
⁶ Institute for Computational Engineering and Science and Department of Chemistry, University of Texas at Austin, Austin, TX, 78712, USA.
⁷ Department of Surgery, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center University of Missouri, 1201 Rollins Street, Columbia, MO, 65201, USA. mittlerr@missouri.edu.

^# Contributed equally.

Abstract

Cell Penetrating Peptides (CPPs) are promising anticancer and antimicrobial drugs. We recently reported that a peptide derived from the human mitochondrial/ER membrane-anchored NEET protein, Nutrient Autophagy Factor 1 (NAF-1; NAF-1^44-67), selectively permeates and kills human metastatic epithelial breast cancer cells (MDA-MB-231), but not control epithelial cells. As cancer cells alter their phenotype during growth and metastasis, we tested whether NAF-1^44-67 would also be efficient in killing other human epithelial breast cancer cells that may have a different phenotype. Here we report that NAF-1^44-67 is efficient in killing BT-549, Hs 578T, MDA-MB-436, and MDA-MB-453 breast cancer cells, but that MDA-MB-157 cells are resistant to it. Upon closer examination, we found that MDA-MB-157 cells display a high content of intracellular vesicles and cellular protrusions, compared to MDA-MB-231 cells, that could protect them from NAF-1^44-67. Inhibiting the formation of intracellular vesicles and dynamics of cellular protrusions of MDA-MB-157 cells, using a protein translation inhibitor (the antibiotic Cycloheximide), rendered these cells highly susceptible to NAF-1^44-67, suggesting that under certain conditions, the killing effect of CPPs could be augmented when they are applied in combination with an antibiotic or chemotherapy agent. These findings could prove important for the treatment of metastatic cancers with CPPs and/or treatment combinations that include CPPs.

Grants and funding

R01 GM111364/GM/NIGMS NIH HHS/United States