Abstract
Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treating C6 rat glioblastoma cells with cobalt chloride caused an up-regulation of the enzyme expression, while further elevation of hypoxic stress caused the enzyme aggregation concomitantly with cell death. Reduction or elevation of GAPDH performed with the aid of specific shRNAs resulted in the augmentation of the tumorigenicity of C6 cells or their sensitization to hypoxic stress. Another hypoxia-regulated protein, Hsp70 chaperone, was shown to prevent the aggregation of oxidized GAPDH and to reduce hypoxia-mediated cell death. In order to release the enzyme molecules from the chaperone, we employed its inhibitor, derivative of colchicine. The compound was found to substantially increase aggregation of GAPDH and to sensitize C6 cells to hypoxia both in vitro and in animals bearing tumors with distinct levels of the enzyme expression. In conclusion, blocking the chaperonic activity of Hsp70 and its interaction with GAPDH may become a promising strategy to overcome tumor resistance to multiple environmental stresses and enhance existing therapeutic tools.
Highlights
Hypoxia is a phenomenon accompanying tumor growth and appears to be an essential factor for the progression of lung, colon, and brain cancers [1]
The crucial step of glycolysis is the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, which is catalyzed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH); the amount of the active enzyme is of great importance for the energy metabolism of cancer cells under hypoxic conditions [8]
The function of GAPDH in a tumor cell subjected to hypoxia is controversial; the enzyme is indispensable for cell survival due to promotion of the Warburg effect, whereas oxidative stress damages GAPDH molecules, targeting them to the nucleus and inducing apoptosis and/or converting them to an aggregated state that results in cell death [11,12]
Summary
Hypoxia is a phenomenon accompanying tumor growth and appears to be an essential factor for the progression of lung, colon, and brain cancers [1]. The response of tumor cells to hypoxia is regulated by a few transcription factors, causing significant changes in the homeostasis of cells and often leading to the adaptation of tumor cells to stress [5] One such activator is hypoxia inducible factor alpha (HIF1α), which is known to trigger the transcription of genes involved in angiogenesis, erythropoiesis, proliferation, glycolysis, and other processes essential for survival of cancer cells [6]. Hypoxia is known to increase the number of reactive oxygen and nitrogen species caused by inactivation of the anti-oxidant system, leading to reoxygenation injury that causes chemical modifications of GAPDH, oxidation and nitrosylation [9] Such modifications lead to the inactivation of the enzyme and its transition to the aggregation-prone state [10]. The function of GAPDH in a tumor cell subjected to hypoxia is controversial; the enzyme is indispensable for cell survival due to promotion of the Warburg effect, whereas oxidative stress damages GAPDH molecules, targeting them to the nucleus and inducing apoptosis and/or converting them to an aggregated state that results in cell death [11,12]
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