Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.
Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Yujun
Y
Hao
Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.|Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Yardena
Y
Samuels
Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Qingling
Q
Li
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Dawid
D
Krokowski
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Bo-Jhih
BJ
Guan
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Chao
C
Wang
Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Zhicheng
Z
Jin
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241000, China.
Bohan
B
Dong
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Pharmacognosy, School of Pharmacy, Third Military Medical University, Chongqing 400038, China.
Bo
B
Cao
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Xiujing
X
Feng
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Pharmacy, Suzhou Health College, Suzhou, Jiangsu 215009, China.
Min
M
Xiang
Hathaway Brown School, 19600 North Park Boulevard, Shaker Heights, Ohio 44122, USA.
Claire
C
Xu
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Stephen
S
Fink
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Neal J
NJ
Meropol
Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio 44115, USA.
Yan
Y
Xu
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Ronald A
RA
Conlon
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Sanford
S
Markowitz
Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Kenneth W
KW
Kinzler
Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Victor E
VE
Velculescu
Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Henri
H
Brunengraber
Department of Pathology, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Joseph E
JE
Willis
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Thomas
T
LaFramboise
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Maria
M
Hatzoglou
Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Guo-Fang
GF
Zhang
Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Bert
B
Vogelstein
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Zhenghe
Z
Wang
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007656:Ketoglutaric Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007656:Ketoglutaric Acids; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D005973:Glutamine; D051701:Activating Transcription Factor 4; D000625:Aminooxyacetic Acid; D000255:Adenosine Triphosphate; C000608785:GPT2 protein, human; D000637:Transaminases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D017346:Protein Serine-Threonine Kinases