Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging

Sui Seng Tee; Nathaniel Kim; Quinlan Cullen; Roozbeh Eskandari; Arsen Mamakhanyan; Rami M. Srouji; Rachel Chirayil; Sangmoo Jeong; Mojdeh Shakiba; Edward R. Kastenhuber; Shuibing Chen; Carlie Sigel; Scott W. Lowe; William R. Jarnagin; Craig B. Thompson; Andrea Schietinger; Kayvan R. Keshari

doi:10.1126/sciadv.abm7985

Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging

Sui Seng Tee, Nathaniel Kim, Quinlan Cullen, Roozbeh Eskandari, Arsen Mamakhanyan, Rami M. Srouji, Rachel Chirayil, Sangmoo Jeong, Mojdeh Shakiba, Edward R. Kastenhuber, Shuibing Chen, Carlie Sigel, Scott W. Lowe, William R. Jarnagin, Craig B. Thompson, Andrea Schietinger, Kayvan R. Keshari

Research output: Contribution to journal › Article › peer-review

Abstract

The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-¹³C]-fructose and dissolving in D₂O increased its spin-lattice relaxation time (T₁) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.

Original language	English (US)
Article number	eabm7985
Journal	Science Advances
Volume	8
Issue number	14
DOIs	https://doi.org/10.1126/sciadv.abm7985
State	Published - Apr 2022
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Tee, S. S., Kim, N., Cullen, Q., Eskandari, R., Mamakhanyan, A., Srouji, R. M., Chirayil, R., Jeong, S., Shakiba, M., Kastenhuber, E. R., Chen, S., Sigel, C., Lowe, S. W., Jarnagin, W. R., Thompson, C. B., Schietinger, A., & Keshari, K. R. (2022). Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging. Science Advances, 8(14), [eabm7985]. https://doi.org/10.1126/sciadv.abm7985

Tee, SS, Kim, N, Cullen, Q, Eskandari, R, Mamakhanyan, A, Srouji, RM, Chirayil, R, Jeong, S, Shakiba, M, Kastenhuber, ER, Chen, S, Sigel, C, Lowe, SW, Jarnagin, WR, Thompson, CB, Schietinger, A & Keshari, KR 2022, 'Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging', Science Advances, vol. 8, no. 14, eabm7985. https://doi.org/10.1126/sciadv.abm7985

@article{7b10ffdd224b47588f6c76a2d093400d,

title = "Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging",

abstract = "The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.",

author = "Tee, {Sui Seng} and Nathaniel Kim and Quinlan Cullen and Roozbeh Eskandari and Arsen Mamakhanyan and Srouji, {Rami M.} and Rachel Chirayil and Sangmoo Jeong and Mojdeh Shakiba and Kastenhuber, {Edward R.} and Shuibing Chen and Carlie Sigel and Lowe, {Scott W.} and Jarnagin, {William R.} and Thompson, {Craig B.} and Andrea Schietinger and Keshari, {Kayvan R.}",

note = "Funding Information: This work was supported, in part, by U.S. NIH grants R21CA212958 (K.R.K.), R01CA237466 (K.R.K.), R01CA252037 (K.R.K.), and K99CA226357 (S.J.); by Cancer Center Support Grant P30CA008748 (K.R.K. and C.B.T.); and by grants from the Center for Molecular Imaging and Nanotechnology at Memorial Sloan Kettering Cancer Center (K.R.K.), Tow Foundation (R.E.), Emerson Collective (K.R.K.), the Thompson Family Foundation (K.R.K.), and the Ludwig Center for Basic and Translational Immunology (K.R.K.). Author contributions: S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. designed the study and experiments. S.S.T., N.K., Q.C., R.E., A.M., R.M.S., R.C., S.J., M.S., E.R.K., S.C., C.S., S.W. L., A.S., and W.R.J., performed experiments and provided samples. S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. analyzed the data. S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. wrote the manuscript. Competing interests: C.B.T. is a founder of Publisher Copyright: {\textcopyright} 2022 The Authors, some rights reserved;",

year = "2022",

month = apr,

doi = "10.1126/sciadv.abm7985",

language = "English (US)",

volume = "8",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "14",

}

TY - JOUR

T1 - Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging

AU - Tee, Sui Seng

AU - Kim, Nathaniel

AU - Cullen, Quinlan

AU - Eskandari, Roozbeh

AU - Mamakhanyan, Arsen

AU - Srouji, Rami M.

AU - Chirayil, Rachel

AU - Jeong, Sangmoo

AU - Shakiba, Mojdeh

AU - Kastenhuber, Edward R.

AU - Chen, Shuibing

AU - Sigel, Carlie

AU - Lowe, Scott W.

AU - Jarnagin, William R.

AU - Thompson, Craig B.

AU - Schietinger, Andrea

AU - Keshari, Kayvan R.

N1 - Funding Information: This work was supported, in part, by U.S. NIH grants R21CA212958 (K.R.K.), R01CA237466 (K.R.K.), R01CA252037 (K.R.K.), and K99CA226357 (S.J.); by Cancer Center Support Grant P30CA008748 (K.R.K. and C.B.T.); and by grants from the Center for Molecular Imaging and Nanotechnology at Memorial Sloan Kettering Cancer Center (K.R.K.), Tow Foundation (R.E.), Emerson Collective (K.R.K.), the Thompson Family Foundation (K.R.K.), and the Ludwig Center for Basic and Translational Immunology (K.R.K.). Author contributions: S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. designed the study and experiments. S.S.T., N.K., Q.C., R.E., A.M., R.M.S., R.C., S.J., M.S., E.R.K., S.C., C.S., S.W. L., A.S., and W.R.J., performed experiments and provided samples. S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. analyzed the data. S.S.T., N.K., Q.C., R.E., C.B.T., and K.R.K. wrote the manuscript. Competing interests: C.B.T. is a founder of Publisher Copyright: © 2022 The Authors, some rights reserved;

PY - 2022/4

Y1 - 2022/4

N2 - The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.

AB - The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.

UR - http://www.scopus.com/inward/record.url?scp=85127692059&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85127692059&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abm7985

DO - 10.1126/sciadv.abm7985

M3 - Article

C2 - 35385296

AN - SCOPUS:85127692059

SN - 2375-2548

VL - 8

JO - Science advances

JF - Science advances

IS - 14

M1 - eabm7985

ER -

Ketohexokinase-mediated fructose metabolism is lost in hepatocellular carcinoma and can be leveraged for metabolic imaging

Abstract

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