Abstract
As current classical Hodgkin lymphoma (cHL) treatment strategies have pronounced side-effects, specific inhibition of signaling pathways may offer novel strategies in cHL therapy. Basal autophagy, a regulated catabolic pathway to degrade cell's own components, is in cancer linked with both, tumor suppression or promotion. The finding that basal autophagy enhances tumor cell survival would thus lead to immediately testable strategies for novel therapies. Thus, we studied its contribution in cHL.We found constitutive activation of autophagy in cHL cell lines and primary tissue. The expression of key autophagy-relevant proteins (e.g. Beclin-1, ULK1) and LC3 processing was increased in cHL cells, even in lymphoma cases. Consistently, cHL cells exhibited elevated numbers of autophagic vacuoles and intact autophagic flux. Autophagy inhibition with chloroquine or inactivation of ATG5 induced apoptosis and reduced proliferation of cHL cells. Chloroquine-mediated inhibition of basal autophagy significantly impaired HL growth in-vivo in NOD SCID γc−/− (NSG) mice. We found that basal autophagy plays a pivotal role in sustaining mitochondrial function.We conclude that cHL cells require basal autophagy for growth, survival and sustained metabolism making them sensitive to autophagy inhibition. This suggests basal autophagy as useful target for new strategies in cHL treatment.
Highlights
With an incidence of about 3 new patients per 100.000 persons per year in Western countries, classical Hodgkin lymphoma is one of the most frequent lymphomas. cHL is usually treated with radiation therapy, chemotherapy or hematopoietic stem cell transplantation [1,2,3]
We found compared to GC B cells no up-regulated autophagy markers in BL and DLBCL cell lines (B cell non-Hodgkin lymphoma (B-NHL) cell lines) (Supplemental Figure 1B, 1C)
We showed that basically activated autophagy is a profound requirement for cHL pathology
Summary
With an incidence of about 3 new patients per 100.000 persons per year in Western countries, classical Hodgkin lymphoma (cHL) is one of the most frequent lymphomas. cHL is usually treated with radiation therapy, chemotherapy or hematopoietic stem cell transplantation [1,2,3]. The current goal in the treatment of HL patients is to reduce toxicity but maintain efficacy [4,5,6,7,8]. In this regard, considering the dependency of Hodgkin lymphoma cells on multiple deregulated signaling pathways [9,10,11,12,13,14] targeted cHL therapy, e.g. specific inhibition of signaling pathways, may offer new strategies to improve cHL treatment. It is critical to determine its contributions in one particular tumor
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