title: Homocysteine induces PUMA-mediated mitochondrial apoptosis in SH-SY5Y cells.
abstract: Previous studies have reported that homocysteine induced endoplasmic reticulum (ER) stress in neuronal cells, proposing the underlying mechanism by which it could induce neurotoxicity. Induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP) and activation of caspase-4 by calpain have been suggested to be an important route in inducing apoptosis in response to ER stress. In this study, we investigated the molecular pathway of homocysteine-induced apoptosis in caspase-4 deficient SH-SY5Y human neuroblastoma cells. Homocysteine significantly increased mRNA levels of CHOP and p53, resulting in the upregulation of their downstream target gene, p53 up-regulated modulator of apoptosis (PUMA). In cells treated with homocysteine, Bcl-2-associated X protein (BAX) protein levels, cytochrome c release from the mitochondria, and caspase-9 activation were significantly increased. Consistently, a caspase-9 inhibitor significantly alleviated homocysteine-induced cytotoxicity. Significantly lower BAX mRNA levels and caspase-9 activation were observed in cells transfected with siRNA for PUMA. Taken together, our findings suggest that PUMA would be involved in the possible crosstalk between the ER and the mitochondria in the homocysteine-induced apoptosis of caspase-4 deficient SH-SY5Y cells.
authors.affiliation: Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
authors.forename: Juhae
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
authors.forename: Je Won
authors.initials: JW
authors.lastname: Ko
authors.affiliation: Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea. hye0414@snu.ac.kr.|Research Institute of Human Ecology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea. hye0414@snu.ac.kr.
authors.forename: Young Hye
authors.identifier: 0000-0002-7152-4085
authors.initials: YH
authors.lastname: Kwon
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D006710:Homocysteine
keywords: Apoptosis; ER stress; Homocysteine; Mitochondria; SH-SY5Y cell line; p53 up-regulated modulator of apoptosis (PUMA)