The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells

Emanuele Mocciaro, Claudia Campanella, Rosario Barone, Sonia Emanuele, Marianna Lauricella, Antonella D'Anneo, Celeste Caruso Bavisotto, Francesco Cappello, Antonella Marino Gammazza, Claudia Campanella, Antonella Marino Gammazza, Rosario Barone, Celeste Caruso Bavisotto, Everly Conway De Macario, Stefano Fais, Francesco Cappello, Everly Conway De Macario, Alberto J.L. Macario

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

HSP60 undergoes changes in quantity and distribution in some types of tumors suggesting a participation of the chaperonin in the mechanism of transformation and cancer progression. Suberoylanilide hydroxamic acid (SAHA), a member of a family of histone deacetylase inhibitors (HDACi), has anti-cancer potential but its interaction, if any, with HSP60 has not been elucidated. We investigated the effects of SAHA in a human lung-derived carcinoma cell line (H292). We analysed cell viability and cycle; oxidative stress markers; mitochondrial integrity; HSP60 protein and mRNA levels; and HSP60 post-translational modifications, and its secretion. We found that SAHA is cytotoxic for H292 cells, interrupting the cycle at the G2/M phase, which is followed by death; cytotoxicity is associated with oxidative stress, mitochondrial damage, and diminution of intracellular levels of HSP60; HSP60 undergoes a post-translational modification and becomes nitrated; and nitrated HSP60 is exported via exosomes. We propose that SAHA causes ROS overproduction and mitochondrial dysfunction, which leads to HSP60 nitration and release into the intercellular space and circulation to interact with the immune system. These successive steps might constitute the mechanism of the anti-tumor action of SAHA and provide a basis to design supplementary therapeutic strategies targeting HSP60, which would be more efficacious than the compound alone.
Original languageEnglish
Pages (from-to)28849-28867
Number of pages19
JournalOncotarget
Volume7
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology

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