期刊
CELL DEATH AND DIFFERENTIATION
卷 21, 期 5, 页码 685-695出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.193
关键词
apoptosis; chemotherapy; necroptosis
资金
- European Commission (ArtForce)
- European Research Council
- Agence National de la Recherche (ANR)
- Ligue contre le Cancer (Equipe labellisee)
- Fondation pour la Recherche Medicale (FRM)
- Institut National du Cancer (INCa)
- LabEx LERMIT
- LabEx Immuno-Oncologie
- Fondation de France
- Fondation Bettencourt-Schueller
- AXA Chair for Longevity Research
- Canceropole Ile-de-France
- Paris Alliance of Cancer Research Institutes (PACRI)
- Parkinson's UK
- Wellcome Trust
- Italian Association of Cancer Research (AIRC)
- Telethon Italy
- China Government
- Parkinson's UK [G-0905] Funding Source: researchfish
Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca2+ fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据