TY - JOUR
T1 - Impact of the histone deacetylase inhibitor trichostatin A on active uptake, volume-sensitive release of taurine, and cell fate in human ovarian cancer cells
AU - Lambert, Ian Henry
AU - Nielsen, Dorthe
AU - Stürup, Stefan
PY - 2020
Y1 - 2020
N2 - The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells. TSA has no effect on cisplatin accumulation or cisplatin-induced DNA-damage in A2780WT/A2780RES cells. Tracer technique indicates that TSA inhibits the volume-sensitive organic anion channel (VSOAC) in A2780WT/A2780RES cells and that the activity is restored by exogenous H2O2. As TSA reduces NOX4 mRNA accumulation and concomitantly increases catalase mRNA/protein accumulation, we suggest that TSA increases the antioxidative defense in A2780 cells. Inhibition of the kinase mTOR (rapamycin, palomid, siRNA), which is normally associated with cell growth, reduces VSOAC activity synergistically to TSA. However, as TSA increases mTOR activity (phosphorylation of 4EBP1, S6 kinase, S6, ULK1, SGK1), the effect of TSA on VSOAC activity does not reflect the shift in mTOR signaling. Upregulation of the protein expression and activity of the taurine transporter (TauT) is a phenotypic characteristic of A2780RES cells. However, TSA reduces TauT protein expression in A2780RES cells and activity to values seen in A2780WT cells. It is suggested that therapeutic benefits of TSA in A2780 do not imply facilitation of cisplatin uptake but more likely a synergistic activation of apoptosis/autophagy and reduced TauT activity.
AB - The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells. TSA has no effect on cisplatin accumulation or cisplatin-induced DNA-damage in A2780WT/A2780RES cells. Tracer technique indicates that TSA inhibits the volume-sensitive organic anion channel (VSOAC) in A2780WT/A2780RES cells and that the activity is restored by exogenous H2O2. As TSA reduces NOX4 mRNA accumulation and concomitantly increases catalase mRNA/protein accumulation, we suggest that TSA increases the antioxidative defense in A2780 cells. Inhibition of the kinase mTOR (rapamycin, palomid, siRNA), which is normally associated with cell growth, reduces VSOAC activity synergistically to TSA. However, as TSA increases mTOR activity (phosphorylation of 4EBP1, S6 kinase, S6, ULK1, SGK1), the effect of TSA on VSOAC activity does not reflect the shift in mTOR signaling. Upregulation of the protein expression and activity of the taurine transporter (TauT) is a phenotypic characteristic of A2780RES cells. However, TSA reduces TauT protein expression in A2780RES cells and activity to values seen in A2780WT cells. It is suggested that therapeutic benefits of TSA in A2780 do not imply facilitation of cisplatin uptake but more likely a synergistic activation of apoptosis/autophagy and reduced TauT activity.
KW - apoptosis
KW - autophagy
KW - LRRC8A
KW - TauT
KW - VSOAC
U2 - 10.1152/ajpcell.00460.2019
DO - 10.1152/ajpcell.00460.2019
M3 - Journal article
C2 - 31913698
AN - SCOPUS:85081164744
VL - 318
SP - C581-C597
JO - American Journal of Physiology: Cell Physiology
JF - American Journal of Physiology: Cell Physiology
SN - 0363-6143
IS - 3
ER -