Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF

被引：690

作者：

Haq, Rizwan ^{[1
,2
]}

Shoag, Jonathan ^{[4
]}

Andreu-Perez, Pedro ^{[2
]}

Yokoyama, Satoru ^{[2
,5
]}

Edelman, Hannah ^{[2
]}

Rowe, Glenn C. ^{[4
]}

Frederick, Dennie T. ^{[3
]}

Hurley, Aeron D. ^{[6
]}

Nellore, Abhinav ^{[7
]}

Kung, Andrew L. ^{[8
]}

Wargo, Jennifer A. ^{[3
]}

Song, Jun S. ^{[7
]}

Fisher, David E. ^{[1
,2
]}

Arany, Zolt ^{[4
]}

Widlund, Hans R. ^{[6
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[4] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02116 USA

[5] Toyama Univ, Inst Nat Med, Div Pathogen Biochem, Toyama 9300194, Japan

[6] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[7] Univ Calif San Francisco, Inst Human Genet, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[8] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10032 USA

来源：

CANCER CELL | 2013年 / 23卷 / 03期

关键词：

TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; CONTROLLING MITOCHONDRIAL BIOGENESIS; B-RAF; METASTATIC MELANOMA; HEPATIC GLUCONEOGENESIS; CELL PROLIFERATION; PGC-1; COACTIVATORS; MALIGNANT-MELANOMA; SKELETAL-MUSCLE; CANCER CELLS;

D O I：

10.1016/j.ccr.2013.02.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1 alpha. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1 alpha. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1 alpha and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.

引用

页码：302 / 315

页数：14

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