Inactivation of NF-κB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells

Abstract

Histone deacetylase inhibitors (HDACi) are a new class of anticancer agents that cause growth arrest, differentiation and/or apoptosis in many tumor cells. As acetylation regulates the activity of the anti-apoptotic transcription factor NF-kappaB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-kappaB activation and as a consequence potentiate HDACi-dependent apoptosis in breast cancer cells. We observed that the HDACi suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) induced cell death but also enhanced NF-kappaB-activity. This increase of NF-kappaB activity was strongly reduced by the addition of MG-132. Moreover, MG-132 potentiates the HDACi-induced cell death that was associated with caspase-3 activation, and PARP cleavage. Induction of the stress related kinases JNK and p38 and the up-regulation of p21 and p27 were also observed after co-treatment of cells with HDACi and MG-132. Disruption of the NF-kappaB pathway by BAY 11-7085 or IkappaB-SR mimicked the action of MG-132 in promoting HDACi-induced cell death. Thus, the combined treatment with HDACi and proteasome inhibitors potentiates apoptosis in breast cancer cells representing a novel strategy for breast cancer therapy.

Proteasome Inhibition Reduces Proliferation, Collagen Expression, and Inflammatory Cytokine Production in Nasal Mucosa and Polyp Fibroblasts

“…The induction of this early apoptotic event by proteasome inhibitors has been reported in cancer cells (Ling et al, 2003b;Domingo-Domènech et al, 2008) and human pulmonary fibroblasts (You and Park, 2011). Our results using the caspase inhibitor z-VAD-FMK revealed that the decrease in nasal fibroblast viability provoked by MG262 involved caspase-mediated apoptosis.…”

“…The loss of mitochondrial membrane potential is one of the earliest events that initiates the classic intrinsic pathway of apoptosis (Elmore, 2007), and proteasome inhibitors are known to induce this event in cancer cells (Ling et al, 2003b;Domingo-Domènech et al, 2008). We therefore aimed to investigate whether MG262 provoked the loss of mitochondrial membrane potential in nasal fibroblasts.…”

“…Proteasome inhibitors cause cell-cycle arrest, particularly a G 2 /M arrest, in cancer cells (Ling et al, 2003a;CodonyServat et al, 2006;Domingo-Domènech et al, 2008). The use of synchronized (growth-arrested) cultures showed that this arrest takes place not only in G 2 /M but also in G 0 , G 1 or G 1 /S transition in nasal fibroblasts.…”

Trastuzumab enhances the anti-tumor effects of the histone deacetylase inhibitor sodium butyrate on a HER2-overexpressing breast cancer cell line

“…On one hand, HDACi inhibited the activity of HDACs, which interact with sequence-specific transcriptional factors on p27 Kip1 promoter and deacetylate promoter-bound histones (21)(22)(23)(24)(25)(26)(27). Therefore NaB could directly inhibit the HDACs of the p27 Kip1 promoter to cause an accumulation of acetylated histones for the access of basal transcriptional factors to the promoter, such as activating the binding of SP1 to proximal GC boxes (22)(23)(24), NF-Y to the CCAAT box (24), ectopic E2F to 5'-TTTG/CG/ CCGC-3' sequences (25,28) and repressing the binding of c-Myc to Inr elements (27), NF-κB to 5'-GGGCTTCCCC-3' sequences (27). On the other hand, HDACi may indirectly block the pathway of AKT or ERK and affect the expression of c-Myc and FoxO factors which inhibited p27…”

Apoptosis of Breast Cancer Cells: Modulation of Genes for Glycoconjugate Biosynthesis and Targeted Drug Delivery

“…Targeting mitochondria as a cancer therapeutic strategy is of interest in recent years. Besides recognition of inhibitors of GSL biosynthesis ( l -PPMP, d -PPMNP, and d -PDMP) and DNA biosynthesis (cisplatin) in our laboratory (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) several other different chemicals have been tested as apoptosis inducing agents (via intrinsic mitochondrial or extrinsic receptor pathways) in breast cancer cells Patil et al 2010 ;Banerjee et al 2010Banerjee et al , 2011Shirure et al 2011 ;Cazet et al 2010 ;Jada et al 2008 ;Domingo-Domenech et al 2008 ;Nakagawa et al 2007 ;Nakajima et al 2007 ;Sato-Cerrato et al 2005 ;Balabhadrapatharuni et al 2005 ;Hatasukari et al 2003 ;Chung et al 2002 ;Hansen et al 2000 ;Fromigue et al 2003 ;Elton et al 2000 ;Distefano et al 1998 ;Han et al 1998 ;Schwartz et al 1997 ;Sarkar et al 2007 ;Singh et al 2009 ;Lu et al 2006 ;Somers-Edgar and Rosegren 2009 ;Neuzil et al 2007 ;Fulda et al 1997 ;Li et al 2010a ;Chaouki et al 2010 a;Mullauer et al 2011a ;Kessler et al 2007a ;Laszczyk 2009 ;Bzesk et al 2006a ;Goldoni et al 2008 a;Ellerby et al 1999 ) .…”