HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets

Simple Summary Exploring the impact of heat shock protein (HSP) inhibition in cancer may give new insights into the cellular processes that these molecules sustain to promote cancer survival and may accelerate the discovery of more HSP inhibitors to be introduced in clinical trials. In this study, we explored the expression and role of high-molecular-weight HSP110 in the survival of Primary Effusion Lymphoma (PEL) cells. We found that the proper expression of this HSP is required to prevent lysosomal permeabilization, DNA damage, c-Myc downregulation and STAT3 de-phosphorylation. Indeed, HSP silencing strongly reduces PEL cell survival through the dysregulation of these processes that have been found to be interconnected.Abstract Heat shock proteins (HSPs) are highly expressed in cancer cells and represent a promising target in anti-cancer therapy. In this study, we investigated for the first time the expression of high-molecular-weight HSP110, belonging to the HSP70 family of proteins, in Primary Effusion Lymphoma (PEL) and explored its role in their survival. This is a rare lymphoma associated with KSHV, for which an effective therapy remains to be discovered. The results obtained from this study suggest that targeting HSP110 could be a very promising strategy against PEL, as its silencing induced lysosomal membrane permeabilization, the cleavage of BID, caspase 8 activation, downregulated c-Myc, and strongly impaired the HR and NHEJ DNA repair pathways, leading to apoptotic cell death. Since chemical inhibitors of this HSP are not commercially available yet, this study encourages a more intense search in this direction in order to discover a new potential treatment that is effective against this and likely other B cell lymphomas that are known to overexpress HSP110.