TY - JOUR
T1 - The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells
AU - Campanella, Claudia
AU - D'Anneo, Antonella
AU - Gammazza, Antonella Marino
AU - Bavisotto, Celeste Caruso
AU - Barone, Rosario
AU - Emanuele, Sonia
AU - Lo Cascio, Filippa
AU - Mocciaro, Emanuele
AU - Fais, Stefano
AU - De Macario, Everly Conway
AU - Macario, Alberto J.L.
AU - Cappello, Francesco
AU - Lauricella, Marianna
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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.
AB - 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.
KW - Exosomes
KW - HSP60
KW - Histone deacetylase inhibitor
KW - Oxidative stress
KW - SAHA
UR - http://www.scopus.com/inward/record.url?scp=84969895342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84969895342&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.6680
DO - 10.18632/oncotarget.6680
M3 - Article
C2 - 26700624
AN - SCOPUS:84969895342
SN - 1949-2553
VL - 7
SP - 28849
EP - 28867
JO - Oncotarget
JF - Oncotarget
IS - 20
ER -