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other·oncology, immunology, preclinical research, biomedical research·PMC10468091

Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma

PLOS Pathogens · 10 authors, 3 centres

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TL;DR

Using KSHV-positive B lymphoma cell lines and a xenografted mouse model, researchers demonstrated that latent KSHV infection upregulates FoxO1 and FoxO3, enhancing antioxidant defense and ROS scavenging.

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other

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oncology

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ORIGINAL PAPER

PMC10468091

Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma

PLOS Pathogens

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ABSTRACT

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H 2 O 2 ) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo . Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.

CITATION EXPORT

Jungang Lan, Yeqing Wang, Shusheng Yue et al.. Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma. PLOS Pathogens. (2023). https://doi.org/10.1371/journal.ppat.1011581

AUTHORS

10 · 3 CENTRES

Jungang Lan, Yeqing Wang, Shusheng Yue, Duo Xu, Yinan Li, Xiangyu Peng, Jiao Hu, Enguo Ju, Shanping He, Tingting Li

1State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
2Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
3Harvard University, UNITED STATES