Die Bedeutung von Autophagie in der Pathogenese des klassischen Hodgkin Lymphoms- ein transformierender oder Tumor-suppressiver Prozess?
Zusammenfassung der Projektergebnisse
As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced sideeffects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Autophagy is a regulated catabolic pathway to degrade cell’s own components that is in cancer linked with both, tumor suppression or tumor promotion, depending on the type of cancer and upon the stage of the disease. The finding that autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies because a number of drugs affecting autophagy are available. Thus, we studied in this project its contribution in cHL. We found constitutive activation of autophagy in cHL cell lines and primary cHL tissue. The expression of several key autophagy-relevant proteins tested (e.g. Beclin-1, ULK1/2, ATG5, PINK-1, Park2) and LC3 processing from LC3I to LC3II was increased in cHL cell lines, and primary tissue. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux, as evidenced by low levels of p62, and co-localization of LC3II with lysosomal markers. It seems that constitutive autophagy activation is a unique feature of cHL among B-cell lymphomas, as autophagy was not basically activated in BL and DLBCL cell lines and BL cases. Autophagy inhibition with chloroquine or inactivation of the key autophagy marker ATG5 induced apoptosis, reduced proliferation and impaired energy conversion in cHL cells. cHL cell lines showed strong dependency on oxidative phosphorylation (OXPHOS) for energy conversion and highly efficient mitochondria, as compared with normal B cells. Chloroquine-treatment reduced OXPHOS energy conversion and increased lactate production rates indicating a switch from oxidative to non-oxidative energy metabolism. We further found that autophagy plays a role in cellular ROS-control of cHL cells. After chloroquine treatment, cHL cells demonstrated increased ROS levels (whole cellular and mitochondrial) causing DNA, lipid and protein damage. Autophagy is probably regulated mTOR-independently by the IP3 pathway with the IP3R being a central part. IP3R stimulation reduced significantly the number of autophagosomes in cHL cells. The strong abundance of several key autophagy proteins did not exclude that activating mutations would exist in cHL that activate autophagy gene expression and finally contribute to autophagy activation. However, such genetic features are normally specific events that would lead to up-regulation of only single autophagy-relevant proteins. Thus, we now analyze the role of microRNAs in the regulation of autophagy protein expression, as they are able to induce multiple genes/proteins possibly leading to upregulation of several autophagy markers. We conclude from our results that cHL cells require autophagy for growth, survival, sustained energy metabolism and cellular ROS-control making them sensitive to autophagy inhibition. This suggests autophagy as useful target for new strategies in cHL treatment.
Projektbezogene Publikationen (Auswahl)
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Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. 9th International symposium on Hodgkin Lymphoma 2013
K. Birkenmeier, S. Droese, I. Wittig, R. Winkelmann, S. Hartmann, C. Doering, T. Wenz, A. Reichert, U. Brandt, and M. L. Hansmann
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Autophagy is pivotal for Hodgkin’s and Reed-Sternberg cells’ survival and growth revealing a new strategy for lymphoma treatment. International meeting of the German Society for cell biology 2014
K. Birkenmeier, K. Moll, S. Newrzela, S. Dröse, S. Hartmann, and M. L. Hansmann
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Autophagy is pivotal for Hodgkin’s and Reed-Sternberg cells’ survival and growth revealing a new strategy for lymphoma treatment. 99th annual meeting of the German Society of Pathology 2015
K. Birkenmeier, K. Moll, S. Newrzela, S. Dröse, S. Hartmann, and M. L. Hansmann
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Burkitt lymphoma cells require autophagy to dispense with oxidative stress. 99th annual meeting of the German Society of Pathology 2015
K. Birkenmeier, S, Hartmann, M. L. Hansmann
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Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. EMBO workshop “Mitochondria Apoptosis and Cancer (MAC) 2015”
K. Birkenmeier, S. Droese, I. Wittig, R. Winkelmann, S. Hartmann, C. Doering, T. Wenz, A. Reichert, U. Brandt, and M. L. Hansmann
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Autophagy is pivotal for Hodgkin and Reed-Sternberg cells’ survival and growth revealing a new strategy for lymphoma treatment. Oncotarget. 2016 Jul 19;7(29):46579-46588
Birkenmeier K, Moll K, Newrzela S, Hartmann S, Dröse S, Hansmann ML
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Hodgkin and Reed- Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. Int J Cancer; 18 Jan 2016
K. Birkenmeier, S. Droese, I. Wittig, V. Käfer, R. Winkelmann, S. Hartmann, C. Doering, T. Wenz, A. Reichert, U. Brandt, and M. L. Hansmann
