Abstract

Despite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells. However, the mechanisms of glycolysis inhibition and their relationship with thermoresistance remain to be explored. In this study, metabolomic analysis indicated the downregulation of glycolytic metabolites in SKOV3 cells after hyperthermia. Proteomic and pathway analyses predicted that the ubiquitin pathway was explicitly activated in resistant SKOV3 cells, compared with hyperthermia-sensitive A2780 cells, and STUB1, a ubiquitin ligase, potentially targeted PKM, a glycolytic rate-limiting enzyme. PKM is degraded via ubiquitination upon hyperthermia. Although glycolysis is inactivated by hyperthermia, ATP production is maintained. We observed that oxygen consumption and mitochondrial membrane potential were activated in SKOV3 cells but suppressed in A2780 cells. The activation of mitochondria could compensate for the loss of ATP production due to the suppression of glycolysis by hyperthermia. Although the physiological significance has not yet been elucidated, our results demonstrated that metabolomic adaptation from the Warburg effect to mitochondrial oxidative phosphorylation could contribute to thermoresistance in ovarian and uterine cancer cells.

Highlights

  • Despite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood

  • We previously demonstrated that glycolysis enzymes were downregulated explicitly in hyperthermia-resistant SKOV3 cells after hyperthermia compared to hyperthermia-sensitive A2780 ­cells[8]

  • Because a remarkable decrease in glycolytic enzymes was observed in SKOV3 cells after hyperthermia in a previous ­study[8], we further examined metabolites in the glycolysis pathway (Fig. 1C)

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Summary

Introduction

Despite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. Proteomic analysis revealed that glycolysis-related enzymes were downregulated after hyperthermia in resistant human ovarian SKOV3 cells. Because a remarkable decrease in glycolytic enzymes was observed in SKOV3 cells after hyperthermia in a previous ­study[8], we further examined metabolites in the glycolysis pathway (Fig. 1C). The proteins involved in the ubiquitination pathway were found to be most upregulated in SKOV3 cells (Fig. 2B).

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