期刊
CANCER LETTERS
卷 414, 期 -, 页码 136-146出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.10.047
关键词
Cisplatin; Necroptosis; Lung cancer; PITP alpha
类别
资金
- National Natural Science Foundation of China [31371405]
- National Basic Research Program of China [2015CB553701]
Necroptosis has been reported to be involved in cisplatin-induced cell death, but the mechanisms underlying the occurrence of necroptosis are not fully elucidated. In this study, we show that apart from apoptosis, cisplatin induces necroptosis in A549 cells. The alleviation of cell death by two necroptosis inhibitors-necrostatin-1 (Nec-1) and necrosulfonamide (NSA), and the phosphorylation of mixed lineage kinase domain-like protein (MLKL) at serine 358, suggest the involvement of receptor-interacting protein kinase 1 (RIPK1)-RIPK3-MLKL signaling in cisplatin-treated A549 cells. Additionally, the initiation of cisplatin-induced necroptosis relies on autocrine tumor necrosis factor alpha (TNF-alpha). Furthermore, we present the first evidence that phosphatidylinositol transfer protein alpha (PITP alpha) is involved in MLKL-mediated necroptosis by interacting with the N terminal MLKL on its sixth helix and the preceding loop, which facilitates MLKL oligomerization and plasma membrane translocation in necroptosis. Silencing of PITP alpha expression interferes with MLKL function and reduces cell death. Our data elucidate that cisplatin-treated lung cancer cells undergo a new type of programmed cell death called necroptosis and shed new light on how MLKL translocates to the plasma membrane. (C) 2017 Elsevier B.V. All rights reserved.
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