IR@PKUHSC  > 北京大学临床肿瘤学院  > 分子肿瘤学研究室
学科主题临床医学
Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth
Sun, Qian1,2,3; Chen, Xinxin1,2,3; Ma, Jianhui4; Peng, Haiyong1,2,3; Wang, Fang1,2,3; Zha, Xiaojun1,2,3; Wang, Yanan1,2,3; Jing, Yanling1,2,3; Yang, Hongwang1,2,3; Chen, Rongrong1,2,3; Chang, Long1,2,3; Zhang, Yu5,6; Goto, June7,8; Onda, Hiroaki9; Chen, Tong10; Wang, Ming-Rong5,6; Lu, Youyong11; You, Han4; Kwiatkowski, David7,8; Zhang, Hongbing1,2,3
关键词PTEN tuberous sclerosis 1 hexokinase II lactate dehydrogenase-B glyceraldehyde 3-phosphate dehydrogenase
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011-03-08
DOI10.1073/pnas.1014769108
108期:10页:4129-4134
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]TUBEROUS SCLEROSIS COMPLEX ; CELL-GROWTH ; SIGNALING PATHWAYS ; RENAL-CARCINOMA ; VEGF EXPRESSION ; CANCER-CELLS ; NULL-CELLS ; MTOR ; TSC2 ; METABOLISM
英文摘要

Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1 alpha (HIF1 alpha)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1 alpha/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.

语种英语
WOS记录号WOS:000288120400059
项目编号30788004 ; 2009CB522202 ; 2009CB522203 ; B08007
资助机构National Natural Science Foundation of China ; National Basic Research Program of China 973 Program ; Ministry of Education of China
引用统计
被引频次:276[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65397
专题北京大学临床肿瘤学院_分子肿瘤学研究室
作者单位1.Peking Union Med Coll, Inst Basic Med Sci, Dept Physiol & Pathophysiol, State Key Lab Med Mol Biol, Beijing 100005, Peoples R China
2.Peking Union Med Coll, Sch Basic Med, Beijing 100005, Peoples R China
3.Chinese Acad Med Sci, Beijing 100005, Peoples R China
4.Xia Men Univ, Sch Life Sci, Xiamen 361005, Peoples R China
5.Chinese Acad Med Sci, Beijing 100021, Peoples R China
6.Peking Union Med Coll, Canc Inst Hosp, State Key Lab Mol Oncol, Beijing 100021, Peoples R China
7.Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
8.Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA
9.Jackson Lab, Mouse Genome Informat Team, Bar Harbor, ME 04609 USA
10.Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA
11.Peking Univ, Sch Oncol, Beijing Canc Hosp Inst, Mol Oncol Lab, Beijing 100142, Peoples R China
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GB/T 7714
Sun, Qian,Chen, Xinxin,Ma, Jianhui,et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2011,108(10):4129-4134.
APA Sun, Qian.,Chen, Xinxin.,Ma, Jianhui.,Peng, Haiyong.,Wang, Fang.,...&Zhang, Hongbing.(2011).Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,108(10),4129-4134.
MLA Sun, Qian,et al."Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 108.10(2011):4129-4134.
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