1887

Journal of General Virology header logo

Volume 102, Issue 11

Hesperetin inhibits KSHV reactivation and is reversed by HIF1α overexpression No Access

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic virus, has two life cycle modes: the latent and lytic phases. KSHV lytic reactivation is important for both viral propagation and KSHV-induced tumorigenesis. The KSHV replication and transcription activator (RTA) protein is essential for lytic reactivation. Hesperetin, a citrus polyphenolic flavonoid, has antioxidant, anti-inflammatory, hypolipidemic, cardiovascular and anti-tumour effects. However, the effects of hesperetin on KSHV replication and KSHV-induced tumorigenesis have not yet been reported. Here, we report that hesperetin induces apoptotic cell death in BCBL-1 cells in a dose-dependent manner. Hesperetin inhibits KSHV reactivation and reduces the production of progeny virus from KSHV-harbouring cells. We also confirmed that HIF1α promotes the RTA transcriptional activities and lytic cycle-refractory state of KSHV-infected cells. Hesperetin suppresses HIF1α expression to inhibit KSHV lytic reactivation. These results suggest that hesperetin may represent a novel strategy for the treatment of KSHV infection and KSHV-associated lymphomas.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): hesperetin , HIF1α , KSHV , lytic activation and RTA
© 2021 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001686
2021-11-08
2024-04-25
Loading full text...

Full text loading...

References

  1. Decker LL, Shankar P, Khan G, Freeman RB, Dezube BJ et al. The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients. J Exp Med 1996; 184:283–288 [View Article] [PubMed]
     [Google Scholar]
  2. Rose TM, Bruce AG, Barcy S, Fitzgibbon M, Matsumoto LR et al. Quantitative RNAseq analysis of Ugandan KS tumors reveals KSHV gene expression dominated by transcription from the LTd downstream latency promoter. Plos Pathog 2018; 14:e1007441
     [Google Scholar]
  3. Wang X, Chen W, Yuan Y. KSHV enhances mesenchymal stem cell homing and promotes KS-like pathogenesis. Virology 2020; 549:5–12S0042-6822(20)30139-2 [View Article] [PubMed]
     [Google Scholar]
  4. Carbone A, Gloghini A. PEL and HHV8-unrelated effusion lymphomas: classification and diagnosis. Cancer 2008; 114:225–227 [View Article] [PubMed]
     [Google Scholar]
  5. Gonnella R, Yadav S, Gilardini Montani MS, Granato M, Santarelli R et al. Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells. Free Radical Biology and Medicine 2017; 112:327–335 [View Article]
     [Google Scholar]
  6. Chadburn A, Hyjek EM, Tam W, Liu Y, Rengifo T et al. Immunophenotypic analysis of the Kaposi sarcoma herpesvirus (KSHV; HHV-8)-infected B cells in HIV+ multicentric Castleman disease (MCD). Histopathology 2008; 53:513–524 [View Article] [PubMed]
     [Google Scholar]
  7. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Corrigendum: Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol 2017; 8:1572 [View Article] [PubMed]
     [Google Scholar]
  8. Tan B, Liu H, Zhang S, da Silva SR, Zhang L et al. Viral and cellular N(6)-methyladenosine and N(6),2’-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol 2018; 3:108–120 [View Article] [PubMed]
     [Google Scholar]
  9. Broussard G, Damania B. Regulation of KSHV Latency and Lytic Reactivation. Viruses 2020; 12:E1034 [View Article] [PubMed]
     [Google Scholar]
  10. El-Mallawany NK, Mehta PS, Kamiyango W, Villiera J, Peckham-Gregory EC et al. KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions. Int J Cancer 2019; 144:110–116 [View Article] [PubMed]
     [Google Scholar]
  11. Granato M, Gilardini Montani MS, Romeo MA, Santarelli R, Gonnella R et al. Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation. Cell Signal 2017; 40:239–247S0898-6568(17)30256-5 [View Article] [PubMed]
     [Google Scholar]
  12. Granato M, Santarelli R, Filardi M, Gonnella R, Farina A et al. The activation of KSHV lytic cycle blocks autophagy in PEL cells. Autophagy 2015; 11:1978–1986 [View Article] [PubMed]
     [Google Scholar]
  13. Shaw RN, Arbiser JL, Offermann MK. Valproic acid induces human herpesvirus 8 lytic gene expression in BCBL-1 cells. Aids 2000; 14:899–902 [View Article] [PubMed]
     [Google Scholar]
  14. He M, Cheng F, da Silva SR, Tan B, Sorel O et al. Molecular biology of KSHV in relation to HIV/AIDS-associated oncogenesis. Cancer Treat Res 2019; 177:23–62 [View Article] [PubMed]
     [Google Scholar]
  15. Hughes DJ, Wood JJ, Jackson BR, Baquero-Perez B, Whitehouse A. NEDDylation is essential for Kaposi’s sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target. Plos Pathog 2015; 11:e1004771 [View Article]
     [Google Scholar]
  16. Dittmer DP, Damania B. Kaposi’s Sarcoma-Associated Herpesvirus (KSHV)-Associated Disease in the AIDS Patient: An Update. Cancer Treat Res 2019; 177:63–80 [View Article] [PubMed]
     [Google Scholar]
  17. Lange P, Damania B. Kaposi Sarcoma-Associated Herpesvirus (KSHV). Trends Microbiol 2020; 28:236–237S0966-842X(19)30261-6 [View Article] [PubMed]
     [Google Scholar]
  18. Abere B, Mamo TM, Hartmann S, Samarina N, Hage E et al. The Kaposi’s sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target. Plos Pathog 2017; 13:e1006639 [View Article] [PubMed]
     [Google Scholar]
  19. Cavallin LE, Goldschmidt-Clermont P, Mesri EA. Molecular and cellular mechanisms of KSHV oncogenesis of Kaposi’s sarcoma associated with HIV/AIDS. Plos Pathog 2014; 10:e1004154
     [Google Scholar]
  20. Musumeci L, Maugeri A, Cirmi S, Lombardo GE, Russo C et al. Citrus fruits and their flavonoids in inflammatory bowel disease: an overview. Nat Prod Res 2020; 34:122–136 [View Article] [PubMed]
     [Google Scholar]
  21. Zhao C, Wang F, Lian Y, Xiao H, Zheng J. Biosynthesis of citrus flavonoids and their health effects. Crit Rev Food Sci Nutr 2020; 60:566–583 [View Article] [PubMed]
     [Google Scholar]
  22. Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM et al. Effect of hesperidin on cardiovascular disease risk factors: the role of intestinal microbiota on hesperidin bioavailability. Nutrients 2020; 12:E1488 [View Article] [PubMed]
     [Google Scholar]
  23. de F, Oliveira JMP, Santos C, Fernandes E. Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine 2020; 73:152887S0944-7113(19)30057-1 [View Article] [PubMed]
     [Google Scholar]
  24. Zheng M, Lu S, Xing J. Enhanced antioxidant, anti-inflammatory and alpha-glucosidase inhibitory activities of citrus hesperidin by acid-catalyzed hydrolysis. Food Chem 2021; 336:127539S0308-8146(20)31401-1 [View Article] [PubMed]
     [Google Scholar]
  25. Hermawan A, Putri H, Utomo RY. Comprehensive bioinformatics study reveals targets and molecular mechanism of hesperetin in overcoming breast cancer chemoresistance. Mol Divers 2020; 24:933–947 [View Article] [PubMed]
     [Google Scholar]
  26. Khan A, Ikram M, Hahm JR, Kim MO. Antioxidant and anti-inflammatory effects of citrus flavonoid hesperetin: special focus on neurological disorders. Antioxidants (Basel) 2020; 9:E609 [View Article] [PubMed]
     [Google Scholar]
  27. Kong W, Ling X, Chen Y, Wu X, Zhao Z et al. Hesperetin reverses Pglycoproteinmediated cisplatin resistance in DDPresistant human lung cancer cells via modulation of the nuclear factorkappaB signaling pathway. Int J Mol Med 2020; 45:1213–1224 [View Article] [PubMed]
     [Google Scholar]
  28. Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL et al. KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis 2015; 18:477–488 [View Article] [PubMed]
     [Google Scholar]
  29. Haque M, Davis DA, Wang V, Widmer I, Yarchoan R. Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia. J Virol 2003; 77:6761–6768 [View Article] [PubMed]
     [Google Scholar]
  30. Singh RK, Lamplugh ZL, Lang F, Yuan Y, Lieberman P et al. KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. Plos Pathog 2019; 15:e1008025
     [Google Scholar]
  31. Vieira J, O’Hearn PM. Use of the red fluorescent protein as a marker of Kaposi’s sarcoma-associated herpesvirus lytic gene expression. Virology 2004; 325:225–240 [View Article] [PubMed]
     [Google Scholar]
  32. Guito J, Lukac DM. KSHV Rta promoter specification and viral reactivation. Front Microbiol 2012; 3:30 [View Article] [PubMed]
     [Google Scholar]
  33. Cai Q, Lan K, Verma SC, Ha Si, Lin D et al. Kaposi’s sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions. J Virol 2006; 80:7965–7975 [View Article] [PubMed]
     [Google Scholar]
  34. He P, Ma J, Liu Y, Deng H, Dong W. Hesperetin promotes cisplatin-induced apoptosis of gastric cancer in vitro and in vivo by upregulating PTEN expression. Front Pharmacol 2020; 11:1326 [View Article] [PubMed]
     [Google Scholar]
  35. Zarebczan B, Pinchot SN, Kunnimalaiyaan M, Chen H. Hesperetin, a potential therapy for carcinoid cancer. Am J Surg 2011; 201:329–332 [View Article] [PubMed]
     [Google Scholar]
  36. Ma Y, He Y, Yin T, Chen H, Gao S et al. Metabolism of phenolic compounds in LPS-stimulated Raw264.7 cells can impact their anti-inflammatory efficacy: indication of hesperetin. J Agric Food Chem 2018; 66:6042–6052 [View Article] [PubMed]
     [Google Scholar]
  37. Lin Z, Fu C, Yan Z, Wu Y, Zhan J et al. The protective effect of hesperetin in osteoarthritis: an in vitro and in vivo study. Food Funct 2020; 11:2654–2666 [View Article] [PubMed]
     [Google Scholar]
  38. Scoditti E. Neuroinflammation and neurodegeneration: the promising protective role of the citrus flavanone hesperetin. Nutrients 2020; 12:E2336 [View Article] [PubMed]
     [Google Scholar]
  39. Trivedi PP, Kushwaha S, Tripathi DN, Jena GB. Cardioprotective effects of hesperetin against doxorubicin-induced oxidative stress and DNA damage in rat. Cardiovasc Toxicol 2011; 11:215–225 [View Article] [PubMed]
     [Google Scholar]
  40. Sonnenblick A, Agbor-Tarh D, de Azambuja E, Hultsch S, Izquierdo M et al. STAT3 activation in HER2-positive breast cancers: Analysis of data from a large prospective trial. Int J Cancer 2020
     [Google Scholar]
  41. Sreenivasan L, Wang H, Yap SQ, Leclair P, Tam A et al. Autocrine IL-6/STAT3 signaling aids development of acquired drug resistance in Group 3 medulloblastoma. Cell Death Dis 2020; 11:1035 [View Article] [PubMed]
     [Google Scholar]
  42. Tarakanova VL, Molleston JM, Goodwin M, Virgin HW t. MHV68 complement regulatory protein facilitates MHV68 replication in primary macrophages in a complement independent manner. Virology 2010; 396:323–328 [View Article] [PubMed]
     [Google Scholar]
  43. Tung KL, Wu YT, Liu C, Lin SC, Wu CH et al. EBV Rta-induced IL-6 Promotes Migration of Bystander Tumor Cells Through IL-6R/JAK/STAT3 Pathway In Vitro. Anticancer Res 2020; 40:3255–3264 [View Article] [PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001686
Loading
Hesperetin inhibits KSHV reactivation and is reversed by HIF1α overexpression
J. Gen. Virol. 102, 001686 (2021); https://doi.org/10.1099/jgv.0.001686
/content/journal/jgv/10.1099/jgv.0.001686
/content/journal/jgv/10.1099/jgv.0.001686
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error