p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
复制标题
p62/SQSTM1在头部和颈部的鳞状细胞癌中积累预测对磷脂酰肌醇3-激酶途径抑制剂的敏感性。
DOI：
10.1371/journal.pone.0090171
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Cohen EE
中科院分区：
文献类型：
--
作者：
Kuo WL;Sharifi MN;Lingen MW;Ahmed O;Liu J;Nagilla M;Macleod KF;Cohen EE
磷酸肌醇-3激酶（PI 3 K）通路在头颈部鳞状细胞癌（SCCHN）中高度失调。虽然PI 3 K/AKT通路的抑制剂正在癌症中开发，但它们的功效似乎与通路基因中突变或扩增的存在无关。PI 3 K通路是宏观自噬的主要调节剂，宏观自噬是一种进化上保守的分解代谢过程，其降解细胞物质以促进细胞稳态和在应激下的存活。采用一组SCCHN细胞系，我们观察到PI 3 K/AKT抑制剂的活性与其诱导自噬的能力之间存在显著相关性。更具体地说，对这些抑制剂的抗性与p62/SQSTM 1的积累有关，p62/SQSTM 1是一种在自噬过程中消耗的多效性蛋白，而自噬的丧失首次被发现是由于一种必需的自噬基因ATG 7的沉默。此外，调节ATG 7和p62/SQSTM 1可以调节对PI 3 K/AKT抑制剂的敏感性，强调了自噬和药物敏感性之间的机制联系。对人体组织的分析显示，与正常组织相比，p62/SQSTM 1在相当大比例的癌症样本中进行性积累，这表明缺陷性自噬与SCCHN相关。这些发现通过TCGA数据的分析进一步验证，证实在10.0%的SCCHN样品中存在ATG 7的纯合缺失和mRNA下调。总之，这些数据表明，p62/SQSTM 1水平调节对PI 3 K/AKT抑制剂的敏感性;癌症通过表观遗传修饰进行自噬的能力不同，当缺乏时，积累p62/SQSTM 1;自噬相关蛋白的表达可以作为SCCHN中对PI 3 K/AKT抑制剂耐药的标志物。
The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.
登录
查看更多内容
影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
5.7
作者：
Ghadimi MP;Lopez G;Torres KE;Belousov R;Young ED;Liu J;Brewer KJ;Hoffman A;Lusby K;Lazar AJ;Pollock RE;Lev D
通讯作者：
Lev D
影响因子：
28.2
作者：
Lui VW;Hedberg ML;Li H;Vangara BS;Pendleton K;Zeng Y;Lu Y;Zhang Q;Du Y;Gilbert BR;Freilino M;Sauerwein S;Peyser ND;Xiao D;Diergaarde B;Wang L;Chiosea S;Seethala R;Johnson JT;Kim S;Duvvuri U;Ferris RL;Romkes M;Nukui T;Kwok-Shing Ng P;Garraway LA;Hammerman PS;Mills GB;Grandis JR
通讯作者：
Grandis JR
Atg7 调节 p53 活性以调节代谢应激期间的细胞周期和存活
DOI：
10.1126/science.1218395
发表时间：
2012-04-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lee IH;Kawai Y;Fergusson MM;Rovira II;Bishop AJ;Motoyama N;Cao L;Finkel T
通讯作者：
Finkel T
DOI：
10.1007/978-1-4020-6554-5_9
发表时间：
2008-01-01
期刊：
PROGRAMMED CELL DEATH IN CANCER PROGRESSION AND THERAPY
影响因子：
--
作者：
Bialik, Shani;Kimchi, Adi
通讯作者：
Kimchi, Adi