RETRACTED ARTICLE: Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca2+-dependent pathway in mouse Neuro-2a neuroblastoma cells

Abstract

Apicidin, a fungal metabolite that functions as a histone deacetylase inhibitor, induces apoptosis in cancer cells. We investigated the molecular mechanisms of the anti-cancer effects of apicidin in mouse Neuro-2a neuroblastoma cells. Apicidin induced apoptotic cell death and activation of caspase-12, -9, and -3. Apicidin induced expression of endoplasmic reticulum (ER) stress-associated proteins, including CCAAT/enhancer binding protein homologous protein (CHOP), cleavage of activating transcription factor 6α, and phosphorylation of eukaryotic initiation factor 2α. Inhibition of ER stress by CHOP knockdown or using the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced apicidin-induced cell death. Apicidin induced reactive oxygen species accumulation and mitochondrial membrane potential loss. An antioxidant, N-acetyl cysteine, reduced apicidin-induced cell death, CHOP expression, and mitochondrial dysfunction. In addition, apicidin increased cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate, an antagonist of inositol 1,4,5-trisphosphate receptor, and BAPTA-AM, an intracellular Ca(2+) chelator. 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited apicidin-induced cell death and ER stress. Interestingly, apicidin induced phosphorylation of phospholipase Cγ1 (PLCγ1) and epidermal growth factor receptor (EGFR), and inhibition of PLCγ1 and EGFR reduced cell death and ER stress. Finally, apicidin-induced histone H3 hyperacetylation and reduction of histone deacetylase 2 mRNA expression were not affected by either a PLCγ1 inhibitor, U73122, or the antioxidant, N-acetyl cysteine. Taken together, the results suggest that apicidin induces apoptosis by ER stress and mitochondrial dysfunction via PLCγ1 activation, Ca(2+) release, and reactive oxygen species accumulation in Neuro-2a neuroblastoma cells.

HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

“…Some HDAC inhibitors have been developed for the treatment of cancers, such as apicidin, Gd-metallofullerenol nanomaterial, MS-275, M344, N -hydroxy-7-(2-naphthylthio) heptanomide (HNHA), panobinostat, trans -3,4,5-trihydroxystilbene (resveratrol), romidepsin, S -7-oxo-7-(4-phenylthiazol-2-ylamino)-heptyl) 2-methylpropanethioate (PTACH), sodium butyrate, suberoylanilide hydroxamic acid (SAHA), TMP269, trichostatin A (TSA), valproic acid (VPA), and WJ25591, among others (Table 1) [7,15,17,18,20,21,22,23,24,25,26,27,28]. HDAC inhibitors can suppress cellular proliferation, induce apoptosis, and exert anti-metastatic and anti-angiogenic effects in cancers [29,30,31].…”

“…PTACH and SAHA also enhance ER stress, induce cellular apoptosis, and exert antitumor effects in non-small cell lung cancer (NSCLC) cells [7,17]. SAHA up-regulates ER stress-regulated proteins including ATF4, GRP78, and CCAAT/enhancer-binding protein homologous protein in NSCLC [22]. SAHA treatment rapidly induces sustained eIF2α phosphorylation and enhances cisplatin-induced ER stress-mediated apoptosis in oral squamous cell carcinoma cells; inhibition of ER stress by salubrinal, an inhibitor of eIF2α dephosphorylation, ameliorates this cytotoxicity [28].…”

“…In addition, the proteasome inhibitor MG-132 dramatically sensitizes WJ2559-induced apoptosis of prostate cancer cells and ER stress contributes to the synergistic effect [20]. Apicidin can induce histone H3 hyperacetylation and reduction of HDAD2 mRNA expression [22]. It causes apoptotic cell death and activates caspase-3, caspase-9, and caspase-12 [22].…”

“…Apicidin can induce histone H3 hyperacetylation and reduction of HDAD2 mRNA expression [22]. It causes apoptotic cell death and activates caspase-3, caspase-9, and caspase-12 [22]. In addition, it increases the expression of ER stress-associated proteins, including CCAAT/CHOP, cleavage of activating transcription factor-6α, and phosphorylation of eIF2α in cancer cells [22].…”

Euphorbia factor L2 induces apoptosis in A549 cells through the mitochondrial pathway

“…In this way, the cancer cells are progressively disassembled and then consumed both by neighboring cells and phagocytic cells. Currently, the intrinsic apoptotic mechanism is more widely implicated in cancer pathogenesis22, 25.…”