Department of Life Sciences, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Mol Oncol. 2018 Jun;12(7):1077-1103. doi: 10.1002/1878-0261.12313. Epub 2018 May 19.
Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca , 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.
线粒体 VDAC1 通过转运阴离子、阳离子、ATP、Ca 和代谢物来介导线粒体与细胞其他部分之间的交流，是细胞凋亡的关键参与者。因此，VDAC1 参与了癌症发展的两个重要特征，即能量和代谢重编程以及逃避细胞凋亡。我们之前开发了细胞穿透性的 VDAC1 衍生肽，这些肽与己糖激酶 (HK)、Bcl-2 和 Bcl-xL 相互作用，以阻止这些蛋白的抗凋亡活性并诱导癌细胞死亡，重点是白血病和神经胶质瘤。在这项研究中，我们证明了一组具有遗传特征的癌细胞系对基于 VDAC1 的肽诱导的细胞凋亡的敏感性，这些细胞系在起源和携带突变方面存在差异。非癌细胞系受这些肽的影响较小。此外，我们构建了其他基于 VDAC1 的肽，旨在提高靶向性、选择性和细胞稳定性，包括 R-Tf-D-LP4，它包含转铁蛋白受体内化序列 (Tf)，允许将肽靶向癌细胞，已知癌细胞过度表达转铁蛋白受体。基于 VDAC1 的肽的作用模式涉及 HK 分离，干扰抗凋亡蛋白的作用，从而激活多条途径，导致细胞能量和代谢稳态受损，并诱导细胞凋亡。最后，在神经胶质瘤、肺癌和乳腺癌的异种移植小鼠模型中，R-Tf-D-LP4 抑制肿瘤生长，同时诱导大量癌细胞死亡，包括癌症干细胞。因此，基于 VDAC1 的肽为癌症治疗提供了一个创新的新概念框架。
