A metabolic prosurvival role for PML in breast cancer

被引：238

作者：

Carracedo, Arkaitz ^{[1
,2
,3
,4
]}

Weiss, Dror ^{[1
,2
]}

Leliaert, Amy K. ^{[5
]}

Bhasin, Manoj ^{[6
]}

de Boer, Vincent C. J. ^{[7
]}

Laurent, Gaelle ^{[7
]}

Adams, Andrew C. ^{[8
,9
]}

Sundvall, Maria ^{[1
,2
]}

Song, Su Jung ^{[1
,2
]}

Ito, Keisuke ^{[1
,2
]}

Finley, Lydia S. ^{[7
]}

Egia, Ainara ^{[1
,2
]}

Libermann, Towia ^{[6
]}

Gerhart-Hines, Zachary ^{[10
]}

Puigserver, Pere ^{[10
]}

Haigis, Marcia C. ^{[7
]}

Maratos-Flier, Elefteria ^{[8
,9
]}

Richardson, Andrea L. ^{[11
]}

Schafer, Zachary T. ^{[5
]}

Pandolfi, Pier P. ^{[1
,2
]}

机构：

[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Genet Program, Sch Med,Beth Israel Deaconess Canc Ctr,Dept Med, Boston, MA 02215 USA

[2] Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Genet Program, Sch Med,Beth Israel Deaconess Canc Ctr,Dept Patho, Boston, MA 02215 USA

[3] Basque Fdn Sci, CIC BioGUNE, Bizkaia, Spain

[4] Basque Fdn Sci, IKERBASQUE, Bizkaia, Spain

[5] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA

[6] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Sch Med, Boston, MA 02215 USA

[7] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA

[8] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[9] Beth Israel Deaconess Med Ctr, Dept Endocrinol, Boston, MA 02215 USA

[10] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[11] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2012年 / 122卷 / 09期

关键词：

FATTY-ACID OXIDATION; GENE-EXPRESSION; LIPID-METABOLISM; PPAR-ALPHA; PGC-1-ALPHA; MECHANISMS; PROTECTS; GAMMA; SUSCEPTIBILITY; ACCUMULATION;

D O I：

10.1172/JCI62129

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted. as both a negative regulator of PPAR gamma coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.

引用

页码：3088 / 3100

页数：13

共 82 条

[21] The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD+ [J].