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Abstract

Most cancers are characterized by a high rate of glycolysis and overexpression of mitochondrial-bound isoforms of hexokinase, an enzyme that phosphorylates glucose in an ATP-dependent manner and this commences the first committed step in glucose metabolism. Type II hexokinase (HK II) plays a paramount role in metabolic reprogramming in tumors and its association with the voltage dependent anion channel (VDAC), a major channel for transport of metabolites and ions across the mitochondrial membrane, inhibits apoptosis in cancer cells and is therefore an important therapeutic target. A peptide corresponding to the mitochondrial membrane-binding N-terminal domain of HK II (pHK II) can potentially compete with the endogenous protein for binding to mitochondria and trigger apoptosis. In vitro studies in HeLa cells showed that coupling of pHK II to a short penetration accelerating sequence (Pas: FFLIPKG) enhances the peptide's intracellular delivery and cytosolic release, followed by localization to the mitochondria. Cell viability assays revealed that pHK II-pas was considerably more effective in inhibiting cell growth compared to pHK II alone. Moreover, pHK II-pas displayed an enhanced ability to deplete cellular ATP levels and induce apoptosis. Mitochondrial function analysis showed that exposure to pHK II-pas peptide resulted in a significant decrease in glycolytic capacity and glycolytic reserve, as well as basal oxygen consumption rate (OCR), spare respiratory capacity, and ATP turnover. Importantly, these effects were correlated with HK II release from mitochondria. Thus, the mode of action of pHK II-pas involves release of the HK II protein from the mitochondrial membrane resulting in loss of mitochondrial membrane potential, decreased cellular ATP levels and finally apoptosis. Our results underline the potential of the pHK II-pas cell-penetrating peptide (CPP) as an innovative and effective anti-tumor therapeutic strategy.

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/content/papers/10.5339/qfarc.2016.HBPP3410
2016-03-21
2019-10-21
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarc.2016.HBPP3410
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