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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
HSP110 Inhibition in Primary Effusion Lymphoma Cells: One Molecule, Many Pro-Survival Targets
Roberta Gonnella1, Roberta Zarrella1, Michele Di Crosta1
1Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
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.
Insights
Targeting heat shock protein 110 (HSP110) shows promise for treating Primary Effusion Lymphoma (PEL). Silencing HSP110 triggers cancer cell death by disrupting DNA repair and activating apoptosis, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Heat shock proteins (HSPs) are upregulated in cancer cells, presenting therapeutic targets.
- Primary Effusion Lymphoma (PEL) is a rare KSHV-associated lymphoma lacking effective treatments.
Purpose of the Study:
- To investigate the expression of high-molecular-weight HSP110 in PEL.
- To explore the role of HSP110 in PEL cell survival and identify it as a potential therapeutic target.
Main Methods:
- Investigated HSP110 expression in PEL.
- Utilized gene silencing techniques to assess HSP110's role in cell survival.
- Analyzed downstream effects including lysosomal membrane permeabilization, apoptosis pathways, and DNA repair mechanisms (HR and NHEJ).
Main Results:
- HSP110 is expressed in PEL cells.
- HSP110 silencing led to lysosomal membrane permeabilization and BID cleavage.
- Caspase 8 activation, c-Myc downregulation, and impaired DNA repair (HR and NHEJ) were observed, culminating in apoptotic cell death.
- HSP110 inhibition significantly impaired PEL cell survival.
Conclusions:
- HSP110 is crucial for PEL cell survival.
- Targeting HSP110 represents a promising therapeutic strategy for PEL and potentially other B cell lymphomas overexpressing HSP110.
- Further research into HSP110 chemical inhibitors is encouraged for novel anti-lymphoma treatments.
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