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

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 (H2O2) 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.

Honokiol ameliorates cisplatin-induced acute kidney injury via inhibition of mitochondrial fission.

BACKGROUND AND PURPOSE: Mitochondrial damage and oxidative stress are crucial contributors to the tubular cell injury and death in acute kidney injury. Novel therapeutic strategies targeting mitochondria protection and halting the progression of acute kidney injury are urgently needed. Honokiol is a small-molecule polyphenol that exhibits extraordinary cytoprotective effects, such as anti-inflammatory and anti-oxidative. Thus, we investigated whether honokiol could ameliorate cisplatin-induced acute kidney injury via preventing mitochondrial dysfunction. EXPERIMENTAL APPROACH: Acute kidney injury was induced by cisplatin administration. Biochemical and histological analysis were used to determine kidney injury. The effect of honokiol on mitochondrial function and morphology were determined using immunohistochemistry, transmission electron microscopy, immunoblot and immunofluorescence. To investigate the mechanism by which honokiol alters mitochondrial dynamics, remodelling and resistance to apoptosis, we used transfection experiments, immunoblotting, immunoprecipitation and flow cytometry assay. KEY RESULTS: We demonstrated that the prominent mitochondrial fragmentation occurred in experimental models of cisplatin-induced nephrotoxicity, which was coupled to radical oxygen species (ROS) overproduction, deterioration of mitochondrial function, release of apoptogenic factors and the consequent apoptosis. Honokiol treatment caused notable reno-protection and attenuated of these cisplatin-induced changes. Mechanistically, honokiol treatment recovered the expression of SIRT3 and improved AMPK activity in tubular cells exposure to cisplatin, which preserved the Drp1 phosphorylation at Ser637 and blocked its translocation in mitochondria, consequently preventing mitochondrial fragmentation and subsequent cell injury and death. CONCLUSION AND IMPLICATIONS: Our results indicate that honokiol may protect against cisplatin-induced acute kidney injury by preserving mitochondrial integrity and function by SIRT3/AMPK-dependent mitochondrial dynamics remodelling.