Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier

被引：127

作者：

Bensard, Claire L. ^{[1
]}

Wisidagama, Dona R. ^{[2
]}

Olson, Kristofor A. ^{[1
,6
]}

Berg, Jordan A. ^{[1
]}

Krah, Nathan M. ^{[2
]}

Schell, John C. ^{[1
,7
]}

Nowinski, Sara M. ^{[1
]}

Fogarty, Sarah ^{[1
]}

Bott, Alex J. ^{[1
]}

Wei, Peng ^{[1
]}

Dove, Katja K. ^{[1
]}

Tanner, Jason M. ^{[1
]}

Panic, Vanja ^{[1
]}

Cluntun, Ahmad ^{[1
]}

Lettlova, Sandra ^{[1
]}

Earl, Christian S. ^{[1
]}

Namnath, David F. ^{[1
]}

Vazquez-Arreguin, Karina ^{[3
,8
]}

Villanueva, Claudio J. ^{[1
]}

Tantin, Dean ^{[3
]}

Murtaugh, L. Charles ^{[2
]}

Evason, Kimberley J. ^{[3
,4
]}

Ducker, Gregory S. ^{[1
]}

Thummel, Carl S. ^{[2
]}

Rutter, Jared ^{[1
,5
]}

机构：

[1] Univ Utah, Dept Biochem, Salt Lake City, UT 84132 USA

[2] Univ Utah, Dept Human Genet, Salt Lake City, UT 84132 USA

[3] Univ Utah, Dept Pathol, Salt Lake City, UT 84132 USA

[4] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84132 USA

[5] Univ Utah, Howard Hughes Med Inst, Sch Med, Salt Lake City, UT 84132 USA

[6] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, Austin, TX 78712 USA

[7] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77054 USA

来源：

CELL METABOLISM | 2020年 / 31卷 / 02期

关键词：

STEM-CELL FUNCTION; ADENOMATOUS-POLYPOSIS; MOUSE MODELS; TCA CYCLE; CANCER; DROSOPHILA; HOMEOSTASIS; DIFFERENTIATION; EXPRESSION; OXIDATION;

D O I：

10.1016/j.cmet.2019.11.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrial pyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss of the Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpcl prior to a tumorigenic stimulus doubled the frequency of adenoma formation and produced higher grade tumors. MPC loss was associated with a glycolytic metabolic phenotype and increased expression of stem cell markers. These data suggest that changes in cellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.

引用

页码：284 / +

页数：24

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