The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Activation of Glycogen Synthase Kinase 3β Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity
Abstract
Transformed cells are highly glycolytic and overexpress hexokinase II (HXK II). HXK II is capable of binding to the mitochondria through an interaction with the voltage-dependent anion channel (VDAC), an abundant outer mitochondrial membrane protein. The binding of HXK II to mitochondria has been shown to protect against loss of cell viability. Akt activation inhibits apoptosis partly by promoting the binding of HXK II to the mitochondria, but the mechanism through which Akt accomplishes this has not been characterized. The present report shows that Akt mediates the binding of HXK II to the mitochondria by negatively regulating the activity of glycogen synthase kinase 3β (GSK3β). On inhibition of Akt, GSK3β is activated and phosphorylates VDAC. HXK II is unable to bind VDAC phosphorylated by GSK3β and dissociates from the mitochondria. Inhibition of Akt potentiates chemotherapy-induced cytotoxicity, an effect that is dependent on GSK3β activation and its attendant ability to disrupt the binding of HXK II to the mitochondria. Moreover, agents that can force the detachment of HXK II from mitochondria in the absence of Akt inhibition or GSK3β activation promoted a synergistic increase in cell killing when used in conjunction with chemotherapeutic drugs. Such findings indicate that interference with the binding of HXK II to mitochondria may be a practicable modality by which to potentiate the efficacy of conventional chemotherapeutic agents.
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Cited by
Mitochondrial membrane permeabilization in cell death
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Metadata
- Authors
- Pastorino, J. G., Hoek, J. B., & Shulga, N.
- Venue
- Cancer Research
- Published
- 2005-11-15
- Volume
- 65
- Issue
- 22
- Pages
- 10545-10554
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2131952786
- Cited by
- 398
- References
- 45
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Activation of Glycogen Synthase Kinase 3β Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity. https://app.cochat.ai/papers/10.1158/0008-5472.can-05-1925
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- Pastorino, J. G., Hoek, J. B., & Shulga, N. (2005). Activation of Glycogen Synthase Kinase 3β Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity. Cancer Research. https://doi.org/10.1158/0008-5472.can-05-1925
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