title: Role of oxidative stress, endoplasmic reticulum stress and ERK activation in triptolide-induced apoptosis.
abstract: Since its isolation from Tripterygium wilfordii in 1972, triptolide has been shown to possess potent anticancer activity against a variety of cancers, and has entered phase I clinical trial. It is a diterpenoid triepoxide that acts through multiple molecular targets and signaling pathways. The mitogen-activated protein kinases are well known for their modulation of cell survival and proliferation. In particular, the ERK pathway has a dual role in cell proliferation and cell death. Thus far, data on the effect of triptolide on ERK signaling remain limited. In our current study, we have shown for the first time that ERK activation rather than inhibition occurred in a dose- and time-dependent manner following triptolide treatment in MDA-MB-231 breast cancer cells. ERK activation was crucial in mediating triptolide-induced caspase-dependent apoptosis. Tritpolide-induced ERK activation modulated the expression of the Bcl-2 protein family member Bax but was not involved in the downregulation of Bcl-xL expression. Signals acted upstream of ERK activation included generation of reactive oxygen species (ROS) and endoplasmic reticulum stress predominantly via the PERK‑eIF2α pathway, as the MEK inhibitor U0126 did not inhibit the phosphorylation of PERK and eIF2α or the generation of ROS.
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors: Bee-Jen
authors: BJ
authors: Tan
authors: Gigi N C
authors: GN
authors: Chiu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002986:Clinical Trials as Topic; D004224:Diterpenes / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D004852:Epoxy Compounds / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010616:Phenanthrenes / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D002070:Butadienes; D004224:Diterpenes; D004852:Epoxy Compounds; D015852:Eukaryotic Initiation Factor-2; D009570:Nitriles; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C113580:U 0126; C001899:triptolide; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases