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Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system

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Summary

Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

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Acknowledgments

The authors are very grateful to Professor Nico Dantuma for the kind gift of MelJuSo UbG76V-YFP cells. We also wish to thank Maria Rydåker, Anna Haukkula and Hanna Göransson Kultima at the Uppsala Array Platform for microarray analysis, Sandra Erlund for assistance in the literature survey, and Lena Lenhammar for RNA preparation. This work was supported by unconditional grants from the Lions Cancer Research Fund and a Swedish Institute scholarship for Karolina Lesiak-Mieczkowska.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden

    Jenny Felth & Lars Bohlin

  2. Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden

    Karolina Lesiak-Mieczkowska, Padraig D’Arcy & Stig Linder

  3. Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University, Uppsala, 751 85, Sweden

    Caroline Haglund, Joachim Gullbo, Rolf Larsson, Mårten Fryknäs & Linda Rickardson

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  1. Jenny Felth
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Felth, J., Lesiak-Mieczkowska, K., D’Arcy, P. et al. Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system. Invest New Drugs 31, 587–598 (2013). https://doi.org/10.1007/s10637-012-9902-y

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