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 - Tập 108 Số 10 - Trang 4129-4134 - 2011
Qian Sun1, Xinxin Chen1, Jianhui Ma2, Haiyong Peng1, Sheng Wang1, Xiaojun Zha1, Yanan Wang1, Yanling Jing1, Hong-Wang Yang1, Rongrong Chen1, Long Chang1, Yu Zhang3, June Goto4, Hiroaki Onda5, Tong Chen6, Ming‐Rong Wang3, Youyong Lu7, Han You2, David J. Kwiatkowski4, Hongbing Zhang1
1State Key Laboratory of Medical Molecular Biology, Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China;
2School of Life Sciences, Xia Men University, Xiamen 361005, China;
3State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China
4Division of Translational Medicine, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
5Mouse Genome Informatics Team, The Jackson Laboratory, Bar Harbor, ME 04609;
6Division of Medical Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210; and
7Laboratory of Molecular Oncology, Beijing Cancer Hospital/Institute, School of Oncology, Peking University, Beijing 100142, China

Tóm tắt

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 1α (HIF1α)-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/HIF1α/Myc–hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.

Từ khóa


Tài liệu tham khảo

10.1126/stke.3812007pe14

10.1016/j.cell.2008.08.021

10.1126/science.1160809

10.1126/science.123.3191.309

10.1111/j.1749-6632.2009.05043.x

10.1038/nature06734

10.1038/nature08697

10.1073/pnas.0914845107

10.1016/j.yexcr.2009.06.024

10.1126/science.1188015

10.1126/scisignal.2000998

10.1172/JCI30102

10.1038/onc.2008.238

10.1016/j.ceb.2009.10.007

10.1016/j.cell.2008.04.013

10.1158/0008-5472.CAN-10-1649

10.1016/j.cell.2006.06.055

10.4161/cc.9.9.11358

10.1038/nrc2274

10.1093/hmg/11.5.525

10.1038/ncb840

10.1038/ncb839

10.1016/S0140-6736(03)13044-9

10.1056/NEJMra055323

10.1016/S1097-2765(02)00568-3

10.1056/NEJMoa063564

10.1172/JCI200317222

10.1038/onc.2008.248

10.1158/0008-5472.CAN-10-1649

10.1093/hmg/ddp176

10.1007/s10863-007-9081-2

10.1074/jbc.M611782200

10.1242/jcs.02648

10.1016/j.ccr.2004.06.020

10.1016/j.gde.2009.10.009

10.1126/science.1174229

10.1172/JCI37964

10.1016/j.molcel.2010.06.022

10.1016/j.canlet.2010.08.006

10.1016/j.canlet.2009.08.021

10.1158/0008-5472.CAN-03-2904

10.1074/jbc.M110.121871

10.1172/JCI28984

S Mazurek, Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol, 10.1016/j.biocel.2010.02.005. (2010).

10.1016/S0021-9258(17)31580-6

10.1593/neo.04430

10.1016/S1535-6108(03)00187-9

N El-Hashemite, V Walker, H Zhang, DJ Kwiatkowski, Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res 63, 5173–5177 (2003).

10.1074/jbc.C800170200

10.1096/fj.04-3099fje

10.1038/sj.onc.1208719

10.1016/j.cmet.2007.10.002

10.1016/j.gde.2008.02.003

10.1016/j.cub.2009.09.058

10.1016/j.molcel.2010.05.007

Thông tin
Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 108 Số 10

4129-4134

Thông tin tác giả