Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated
Jungang Chen1, Navneet Goyal2, Lu Dai1
1Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
Abstract:
Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma-associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.
Insights
New ceramide analogs show promise for treating primary effusion lymphoma (PEL), a cancer caused by Kaposi sarcoma-associated herpesvirus (KSHV). These compounds effectively target PEL cells, suppressing tumor growth with minimal toxicity and offering a potential new therapy for this aggressive malignancy.
Area of Science:
- Oncology
- Virology
- Biochemistry
Background:
- Primary effusion lymphoma (PEL) is an aggressive cancer linked to Kaposi sarcoma-associated herpesvirus (KSHV).
- Existing treatments for PEL are limited, highlighting the need for novel therapeutic strategies.
- Sphingolipid metabolism is implicated in KSHV-positive tumor cell survival.
Purpose of the Study:
- To investigate novel ceramide analogs as potential therapeutic agents for PEL.
- To elucidate the mechanism of action of these compounds in targeting PEL cells.
- To identify cellular genes involved in PEL survival regulated by sphingolipid metabolism.
Main Methods:
- Screening of newly synthesized ceramide analogs for anti-PEL activity.
- Assessment of compound effects on PEL apoptosis, cell-cycle arrest, and intracellular ceramide levels.
- In vivo tumor progression studies and comparative transcriptomic analysis.
- Functional validation of identified cellular genes (AURKA, CDCA3).
Main Results:
- Identified ceramide analogs demonstrated significant anti-PEL activity.
- Compounds induced PEL apoptosis, cell-cycle arrest, and increased intracellular ceramide.
- Tumor progression was suppressed in vivo without apparent toxicity.
- Transcriptomic analysis revealed mechanisms of cell death and identified AURKA and CDCA3 as key survival genes regulated by sphingolipid metabolism.
- Increased viral lytic gene expression was observed in PEL cells.
Conclusions:
- Novel ceramide analogs show potent anti-PEL activity by modulating sphingolipid metabolism.
- These compounds represent a promising new therapeutic avenue for KSHV-associated malignancies.
- Targeting sphingolipid metabolism and identified cellular genes offers a framework for future PEL therapies.
