Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:28849-28867. doi: 10.18632/oncotarget.6680

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Abstract

Claudia Campanella1,2,*, Antonella D'Anneo3,*, Antonella Marino Gammazza1,2,*, Celeste Caruso Bavisotto1,2, Rosario Barone1,2, Sonia Emanuele4, Filippa Lo Cascio1, Emanuele Mocciaro1, Stefano Fais5, Everly Conway De Macario6, Alberto J.L. Macario2,6, Francesco Cappello1,2, Marianna Lauricella4

1Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy “Emerico Luna”, University of Palermo, Palermo, Italy

2Euro-Mediterranean Institute of Science and Technology, Palermo, Italy

3Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Palermo, Italy

4Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, Palermo, Italy

5Department of Therapeutic Research and Medicine Evaluation, National Institute of Health (ISS), Rome, Italy

6Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore and IMET, Columbus Center, Baltimore, USA

*These authors have contributed equally to this work

Correspondence to:

Francesco Cappello, email: francapp@hotmail.com

Keywords: histone deacetylase inhibitor, SAHA, HSP60, oxidative stress, exosomes

Received: August 27, 2015     Accepted: November 22, 2015     Published: December 19, 2015

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.

Author Information

Claudia Campanella

Antonella D'Anneo

Antonella Marino Gammazza

Celeste Caruso Bavisotto

Rosario Barone

Sonia Emanuele

Filippa Lo Cascio

Emanuele Mocciaro

Stefano Fais

Everly Conway De Macario

Alberto J.L. Macario

Francesco Cappello
Primary Contact  _

Marianna Lauricella


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