Cytotoxic Drugs Activate KSHV Lytic Cycle in Latently Infected PEL Cells by Inducing a Moderate ROS Increase Controlled by HSF1, NRF2 and p62/SQSTM1

Viruses. 2018 Dec 24;11(1):8. doi: 10.3390/v11010008.

Abstract

Previous studies have indicated that cytotoxic treatments may induce or not activate viral lytic cycle activation in cancer cells latently infected by Kaposi's sarcoma-associated herpesvirus (KSHV). To investigate the molecular mechanisms responsible for such an effect, we compared two cytotoxic treatments able to induce the viral lytic cycle, named 12-O-tetradecanoylphorbol 13-acetate (TPA) (T) in combination with sodium butyrate (B) and bortezomib (BZ), with two cytotoxic treatments that did not activate this process, named metformin (MET) and quercetin (Q). Our results indicated that TB and bortezomib increased levels of oxygen reactive species (ROS) while metformin and quercetin reduced them. The finding that N-acetylcysteine (NAC), a reactive oxigen species (ROS) scavenger, counteracted K-bZIP expression induced by TB or bortezomib, confirmed that an ROS increase played a role in KSHV lytic cycle activation. Moreover, we found that TB and bortezomib up-regulated p62/Sequestosome1(p62/SQSTM1) protein, while metformin and quercetin down-regulated it. p62/SQSTM1 silencing or the inhibition of NF-E2-related factor 2 (NRF2) or Heat Shock Factor 1 (HSF1), that mediate p62/SQSTM1 transcription, also reduced KSHV lytic antigen expression induced by TB or bortezomib. Interestingly, such combination treatments further increased intracellular ROS and cytotoxicity induced by the single TB or bortezomib treatment, suggesting that NRF2, HSF1 and p62/SQSTM1 keep the ROS level under control, allowing primary effusion lymphoma (PEL) cells to continue to survive and KSHV to replicate.

Keywords: Bortezomib; HSF1; KSHV lytic cycle; NRF2; ROS; TPA; butyrate; p62/SQSTM1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Bortezomib / pharmacology
  • Butyric Acid / pharmacology
  • Cell Line, Tumor
  • Down-Regulation
  • Heat Shock Transcription Factors / genetics*
  • Herpesvirus 8, Human / drug effects*
  • Herpesvirus 8, Human / physiology
  • Humans
  • Metformin / pharmacology
  • NF-E2-Related Factor 2 / genetics*
  • Quercetin / pharmacology
  • RNA-Binding Proteins / genetics*
  • Reactive Oxygen Species / metabolism*
  • Sequestosome-1 Protein / genetics*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Trans-Activators / genetics
  • Transcriptional Activation
  • Virus Activation / drug effects
  • Virus Latency / drug effects*

Substances

  • Antineoplastic Agents
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • P62 protein, human
  • RNA-Binding Proteins
  • Reactive Oxygen Species
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Trans-Activators
  • Butyric Acid
  • Bortezomib
  • Metformin
  • Quercetin
  • Tetradecanoylphorbol Acetate