p38MAPK Plays a Crucial Role in Stromal-Mediated Tumorigenesis

被引：154

作者：

Alspach, Elise ^{[1
,4
]}

Flanagan, Kevin C. ^{[1
,4
]}

Luo, Xianmin ^{[1
,4
]}

Ruhland, Megan K. ^{[1
,4
]}

Huang, Hui ^{[1
,4
]}

Pazolli, Ermira ^{[1
]}

Donlin, Maureen J. ^{[5
,6
]}

Marsh, Timothy ^{[8
]}

Piwnica-Worms, David ^{[11
]}

Monahan, Joseph ^{[7
]}

Novack, Deborah V. ^{[2
,3
]}

McAllister, Sandra S. ^{[8
,9
,10
]}

Stewart, Sheila A. ^{[1
,2
,4
]}

机构：

[1] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA

[2] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, BRIGHT Inst, St Louis, MO 63110 USA

[5] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA

[6] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, St Louis, MO USA

[7] Confluence Life Sci Inc, St Louis, MO USA

[8] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Hematol Div, Boston, MA 02115 USA

[9] Harvard Stem Cell Inst, Cambridge, MA USA

[10] Broad Inst Harvard & MIT, Cambridge, MA USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA

来源：

CANCER DISCOVERY | 2014年 / 4卷 / 06期

关键词：

INTERLEUKIN-6; MESSENGER-RNA; EPITHELIAL-CELL GROWTH; MAP KINASE PATHWAY; SECRETORY PHENOTYPE; TUMOR MICROENVIRONMENT; HUMAN FIBROBLASTS; SENESCENCE; CANCER; INHIBITOR;

D O I：

10.1158/2159-8290.CD-13-0743

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Neoplastic cells rely on the tumor microenvironment (TME) for survival and progression factors. Indeed, senescent and cancer-associated fibroblasts (CAF) express factors that promote tumorigenesis that are collectively referred to as the senescence-associated secretory phenotype (SASP). Despite their importance in tumorigenesis, the mechanisms that control TME-derived factor expression remain poorly understood. Here, we address a key unanswered question: how the SASP is sustained in senescent fibroblasts and CAFs. We find that the mitogen-activated protein kinase p38 (p38MAPK) controls AUF1 occupancy on SASP mRNAs and thus controls their stability. The importance of this regulatory mechanism is underscored by our findings that stromalspecific p38MAPK inhibition abrogates the tumor-promoting activities of CAFs and senescent fibroblasts. Our data suggest that targeting SASP mRNA stability through inhibition of p38MAPK will significantly aid the development of clinical strategies to target the TME. (C) 2014 AACR.

引用

页码：716 / 729

页数：14

共 44 条

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