Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity

Laetitia Arzoine, Noam Zilberberg, Ronit Ben-Romano, Varda Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

In brain and tumor cells, the hexokinase isoforms, HK-I and HK-II, bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. The VDAC domains interacting with these anti-apoptotic proteins were recently defined using site-directed mutagenesis. Now, we demonstrate that synthetic peptides corresponding to the VDAC1 N-terminal region and selected sequences bound specifically, in a concentration- and time-dependent manner, to immobilized HK-I, as revealed by real time surface plasmon resonance technology. The same VDAC1-based peptides also detached HK bound to brain or tumor-derived mitochondria. Moreover, expression of the VDAC1-based peptides in cells overexpressing HK-I or HK-II prevented HK-mediated protection against staurosporine-induced release of cytochrome c and subsequent cell death. One loop-shaped VDAC1-based peptide corresponding to a selected sequence and fused to a cell-penetrating peptide entered the cell and prevented the anti-apoptotic effects of HK-I and HK-II. This peptide detached mitochondrial-bound HK better than did the same peptide in its linear form. Both cell-expressed and exogenously added cell-penetrating peptide detached mitochondrial-bound HK-I-GFP. These results point to HK-I and HK-II as promoting tumor cell survival through binding to VDAC1, thereby inhibiting cytochrome c release and apoptotic cell death. Moreover, VDAC1-based peptides interfering with HK-mediated anti-apoptotic activity may potentiate the efficacy of conventional chemotherapeutic agents.

Original languageEnglish
Pages (from-to)3946-3955
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number6
DOIs
StatePublished - 6 Feb 2009

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