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ER‐Dependent Ca ++ ‐Mediated Production of Cytosolic ROS as an Effector for Induction of Mitochondrial Apoptotic Signal and ATM in Gallic Acid‐treated Human Oral Cancer Cell
Author(s) -
Lu YaoCheng,
Lin MengLiang,
Su HongLin,
Chen ShihShun
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1108.7
Subject(s) - apoptosis , thapsigargin , reactive oxygen species , mitochondrial ros , cytosol , microbiology and biotechnology , chemistry , mitochondrion , cytochrome c , kinase , endoplasmic reticulum , biology , biochemistry , enzyme
Release of calcium ( Ca + +) from the endoplasmic reticulum (ER) has been proposed to be involved in induction of apoptosis by oxidative stress. Using ER Ca + + release inhibitor dantrolene and mitochondrial Ca + + uptake inhibitor Ru‐360, we demonstrated that Ca + + release from the ER was associated with loss of mitochondrial membrane potential, increase in reactive oxygen species (ROS), and apoptosis of human oral cancer (OC) cells induced by gallic acid (GA). Chemical chaperone 4‐phenylbutyrate inhibits tunicamycin‐induced induction of 78 kDa glucose‐regulated protein, C/EBP homologous protein and pro‐caspase‐12 cleavage, cytosolic Ca + + increase, and apoptosis, but did not attenuate the increase in cytosolic Ca + + level and apoptosis induced by GA. Ataxia telangiectasia mutated (ATM)‐mediated c‐Jun N‐terminal kinase (JNK) phosphorylation and apoptosis in response to GA was blocked by dantrolene. The specificity of ROS‐mediated ATM activation was confirmed by the treatment of N‐acetylcysteine, an ROS scavenger. Blockade of ATM activation by a specific inhibitor KU55933, short hairpin RNA, or kinase ‐ dead ATM overexpression suppressed JNK phosphorylation but did not completely inhibit cytosolic ROS production, mitochondrial cytochrome c release, pro‐caspase‐3 cleavage, and apoptosis induced by GA. When taken together, these results indicate that GA induces OC cell apoptosis by inducing the activation of mitochondrial apoptotic signal and ATM, likely through ER Ca + + ‐mediated ROS production. Support or Funding Information