Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase C gamma 1-and Ca2+-dependent pathway in mouse Neuro-2a neuroblastoma cells

作者：Choi Ji Hyun; Lee Jung Yeon; Choi A Young; Hwang Keun Young; Choe Wonchae; Yoon Kyung Sik; Ha Joohun; Yeo Eui Ju; Kang Insug^*

来源：Apoptosis, 2012, 17(12): 1340-1358.

DOI：10.1007/s10495-012-0755-9

• Apicidin
• Apoptosis
• Calcium
• ER stress
• Mitochondrial dysfunction
• PLC gamma 1

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 6 alpha, and phosphorylation of eukaryotic initiation factor 2 alpha. 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 Ca2+, which was blocked by 2-aminoethoxydiphenyl borate, an antagonist of inositol 1,4,5-trisphosphate receptor, and BAPTA-AM, an intracellular Ca2+ chelator. 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited apicidin-induced cell death and ER stress. Interestingly, apicidin induced phosphorylation of phospholipase C gamma 1 (PLC gamma 1) and epidermal growth factor receptor (EGFR), and inhibition of PLC gamma 1 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 PLC gamma 1 inhibitor, U73122, or the antioxidant, N-acetyl cysteine. Taken together, the results suggest that apicidin induces apoptosis by ER stress and mitochondrial dysfunction via PLC gamma 1 activation, Ca2+ release, and reactive oxygen species accumulation in Neuro-2a neuroblastoma cells.

• 出版日期2012-12