PMID- 33762003
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240503
IS  - 2049-3002 (Print)
IS  - 2049-3002 (Electronic)
IS  - 2049-3002 (Linking)
VI  - 9
IP  - 1
DP  - 2021 Mar 24
TI  - GLUT5 (SLC2A5) enables fructose-mediated proliferation independent of 
      ketohexokinase.
PG  - 12
LID - 10.1186/s40170-021-00246-9 [doi]
LID - 12
AB  - BACKGROUND: Fructose is an abundant source of carbon and energy for cells to use 
      for metabolism, but only certain cell types use fructose to proliferate. Tumor 
      cells that acquire the ability to metabolize fructose have a fitness advantage 
      over their neighboring cells, but the proteins that mediate fructose metabolism 
      in this context are unknown. Here, we investigated the determinants of 
      fructose-mediated cell proliferation. METHODS: Live cell imaging and crystal 
      violet assays were used to characterize the ability of several cell lines (RKO, 
      H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, 
      DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic 
      ability). Fructose metabolism gene expression was determined by RT-qPCR and 
      western blot for each cell line. A positive selection approach was used to 
      "train" non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq 
      was performed on parental and trained PC3 cells to find key transcripts 
      associated with fructolytic ability. A CRISPR-cas9 plasmid containing 
      KHK-specific sgRNA was transfected in 293T cells to generate KHK(-/-) cells. 
      Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in 
      cells. Metabolic profiling was done with seahorse metabolic flux analysis as well 
      as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 
      2-deoxyglucose in media containing either fructose or glucose. RESULTS: We found 
      that neither the tissue of origin nor expression level of any single gene related 
      to fructose catabolism determine the fructolytic ability. However, cells cultured 
      chronically in fructose can develop fructolytic ability. SLC2A5, encoding the 
      fructose transporter, GLUT5, was specifically upregulated in these cells. 
      Overexpression of GLUT5 in non-fructolytic cells enabled growth in 
      fructose-containing media across cells of different origins. GLUT5 permitted 
      fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase 
      (KHK). CONCLUSIONS: We show that GLUT5 is a robust and generalizable driver of 
      fructose-dependent cell proliferation. This indicates that fructose uptake is the 
      limiting factor for fructose-mediated cell proliferation. We further demonstrate 
      that cellular proliferation with fructose is independent of KHK.
FAU - Liang, Roger J
AU  - Liang RJ
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA.
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
FAU - Taylor, Samuel
AU  - Taylor S
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA.
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
AD  - Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New 
      York, NY, 10065, USA.
AD  - Weill Cornell/Rockefeller/Sloan Kettering Tri-I MD-PhD program, New York, NY, 
      10065, USA.
FAU - Nahiyaan, Navid
AU  - Nahiyaan N
AD  - Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell 
      Medicine, New York, NY, 10065, USA.
FAU - Song, Junho
AU  - Song J
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
FAU - Murphy, Charles J
AU  - Murphy CJ
AD  - Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, 
      NY, 10065, USA.
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 
      10065, USA.
FAU - Dantas, Ezequiel
AU  - Dantas E
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA.
FAU - Cheng, Shuyuan
AU  - Cheng S
AD  - Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New 
      York, NY, 10065, USA.
FAU - Hsu, Ting-Wei
AU  - Hsu TW
AD  - Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New 
      York, NY, 10065, USA.
FAU - Ramsamooj, Shakti
AU  - Ramsamooj S
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA.
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
FAU - Grover, Rahul
AU  - Grover R
AD  - Weill Cornell Medical College, Weill Cornell Medicine, New York, NY, 10065, USA.
FAU - Hwang, Seo-Kyoung
AU  - Hwang SK
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA.
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
FAU - Ngo, Bryan
AU  - Ngo B
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
AD  - Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New 
      York, NY, 10065, USA.
FAU - Cantley, Lewis C
AU  - Cantley LC
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA.
FAU - Rhee, Kyu Y
AU  - Rhee KY
AD  - Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell 
      Medicine, New York, NY, 10065, USA.
FAU - Goncalves, Marcus D
AU  - Goncalves MD
AUID- ORCID: 0000-0002-0784-9248
AD  - Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, 
      New York, NY, 10065, USA. mdg9010@med.cornell.edu.
AD  - Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, 
      NY, 10065, USA. mdg9010@med.cornell.edu.
LA  - eng
GR  - K08 CA230318/NH/NIH HHS/United States
GR  - R35 CA197588/CA/NCI NIH HHS/United States
GR  - R25 AI140472/AI/NIAID NIH HHS/United States
GR  - P50 CA211024/CA/NCI NIH HHS/United States
GR  - R35 CA197588/NH/NIH HHS/United States
GR  - F99CA234950/CA/NCI NIH HHS/United States
GR  - P50 CA211024/NH/NIH HHS/United States
GR  - F99 CA234950/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20210324
PL  - England
TA  - Cancer Metab
JT  - Cancer & metabolism
JID - 101607582
PMC - PMC7992954
OTO - NOTNLM
OT  - Fructose
OT  - GLUT5 (SLC2A5)
OT  - Hexokinase
OT  - Ketohexokinase
OT  - Metabolism
COIS- L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals 
      and is a founder and receives research support from Petra Pharmaceuticals. M.D.G. 
      reports personal fees from Novartis, Petra Pharmaceuticals, and Bayer. He 
      receives research support from Pfizer. L.C.C. and M.D.G. are inventors on patents 
      (pending) for Combination Therapy for PI3K-associated Disease or Disorder, The 
      Identification of Therapeutic Interventions to Improve Response to PI3K 
      Inhibitors for Cancer Treatment, and Anti-Fructose Therapy for Colorectal and 
      Small Intestine Cancers. L.C.C. and M.D.G. are co-founders and shareholders in 
      Faeth Therapeutics. All other authors report no competing interests.
EDAT- 2021/03/26 06:00
MHDA- 2021/03/26 06:01
PMCR- 2021/03/24
CRDT- 2021/03/25 05:40
PHST- 2020/07/13 00:00 [received]
PHST- 2021/02/08 00:00 [accepted]
PHST- 2021/03/25 05:40 [entrez]
PHST- 2021/03/26 06:00 [pubmed]
PHST- 2021/03/26 06:01 [medline]
PHST- 2021/03/24 00:00 [pmc-release]
AID - 10.1186/s40170-021-00246-9 [pii]
AID - 246 [pii]
AID - 10.1186/s40170-021-00246-9 [doi]
PST - epublish
SO  - Cancer Metab. 2021 Mar 24;9(1):12. doi: 10.1186/s40170-021-00246-9.