Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Annemarie Schwab; Aarif Siddiqui; Maria Eleni Vazakidou; Francesca Napoli; Martin Bottcher; Bianca Menchicchi; Umar Raza; Ozge Saatci; Angela M. Krebs; Fulvia Ferrazzi; Ida Rapa; Katja Dettmer-Wilde; Maximilian J. Waldner; Arif B. Ekici; Suhail Ahmed Kabeer Rasheed; Dimitrios Mougiakakos; Peter J. Oefner; Ozgur Sahin; Marco Volante; Florian R. Greten; Thomas Brabletz; Paolo Ceppi

doi:10.1158/0008-5472.CAN-17-2834

Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Annemarie Schwab, Aarif Siddiqui, Maria Eleni Vazakidou, Francesca Napoli, Martin Bottcher, Bianca Menchicchi, Umar Raza, Ozge Saatci, Angela M. Krebs, Fulvia Ferrazzi, Ida Rapa, Katja Dettmer-Wilde, Maximilian J. Waldner, Arif B. Ekici, Suhail Ahmed Kabeer Rasheed, Dimitrios Mougiakakos, Peter J. Oefner, Ozgur Sahin, Marco Volante, Florian R. GretenThomas Brabletz, Paolo Ceppi^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 ( AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR.

Original language	English
Journal	Cancer Research
Volume	78
Issue number	7
Pages (from-to)	1604-1618
Number of pages	15
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-2834
Publication status	Published - Apr 2018
Externally published	Yes

Keywords

A549 Cells
Aldehyde Reductase/genetics
Animals
Cell Line, Tumor
Colonic Neoplasms/pathology
Epithelial-Mesenchymal Transition/genetics
Glucose/metabolism
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
L-Iditol 2-Dehydrogenase/genetics
Lung Neoplasms/pathology
MCF-7 Cells
Mice
RNA Interference
RNA, Small Interfering/genetics
Transforming Growth Factor beta/metabolism

Documents & Links

10.1158/0008-5472.CAN-17-2834

Cite this

Schwab, A., Siddiqui, A., Vazakidou, M. E., Napoli, F., Bottcher, M., Menchicchi, B., Raza, U., Saatci, O., Krebs, A. M., Ferrazzi, F., Rapa, I., Dettmer-Wilde, K., Waldner, M. J., Ekici, A. B., Rasheed, S. A. K., Mougiakakos, D., Oefner, P. J., Sahin, O., Volante, M., ... Ceppi, P. (2018). Polyol pathway links glucose metabolism to the aggressiveness of cancer cells. Cancer Research, 78(7), 1604-1618. https://doi.org/10.1158/0008-5472.CAN-17-2834

@article{f0e10cebff6c4a9a803eb1e14b3d9d4d,

title = "Polyol pathway links glucose metabolism to the aggressiveness of cancer cells",

abstract = "Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 ( AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. {\textcopyright}2018 AACR. ",

keywords = "A549 Cells, Aldehyde Reductase/genetics, Animals, Cell Line, Tumor, Colonic Neoplasms/pathology, Epithelial-Mesenchymal Transition/genetics, Glucose/metabolism, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, L-Iditol 2-Dehydrogenase/genetics, Lung Neoplasms/pathology, MCF-7 Cells, Mice, RNA Interference, RNA, Small Interfering/genetics, Transforming Growth Factor beta/metabolism",

author = "Annemarie Schwab and Aarif Siddiqui and Vazakidou, {Maria Eleni} and Francesca Napoli and Martin Bottcher and Bianca Menchicchi and Umar Raza and Ozge Saatci and Krebs, {Angela M.} and Fulvia Ferrazzi and Ida Rapa and Katja Dettmer-Wilde and Waldner, {Maximilian J.} and Ekici, {Arif B.} and Rasheed, {Suhail Ahmed Kabeer} and Dimitrios Mougiakakos and Oefner, {Peter J.} and Ozgur Sahin and Marco Volante and Greten, {Florian R.} and Thomas Brabletz and Paolo Ceppi",

year = "2018",

month = apr,

doi = "10.1158/0008-5472.CAN-17-2834",

language = "English",

volume = "78",

pages = "1604--1618",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Schwab, A, Siddiqui, A, Vazakidou, ME, Napoli, F, Bottcher, M, Menchicchi, B, Raza, U, Saatci, O, Krebs, AM, Ferrazzi, F, Rapa, I, Dettmer-Wilde, K, Waldner, MJ, Ekici, AB, Rasheed, SAK, Mougiakakos, D, Oefner, PJ, Sahin, O, Volante, M, Greten, FR, Brabletz, T & Ceppi, P 2018, 'Polyol pathway links glucose metabolism to the aggressiveness of cancer cells', Cancer Research, vol. 78, no. 7, pp. 1604-1618. https://doi.org/10.1158/0008-5472.CAN-17-2834

TY - JOUR

T1 - Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

AU - Schwab, Annemarie

AU - Siddiqui, Aarif

AU - Vazakidou, Maria Eleni

AU - Napoli, Francesca

AU - Bottcher, Martin

AU - Menchicchi, Bianca

AU - Raza, Umar

AU - Saatci, Ozge

AU - Krebs, Angela M.

AU - Ferrazzi, Fulvia

AU - Rapa, Ida

AU - Dettmer-Wilde, Katja

AU - Waldner, Maximilian J.

AU - Ekici, Arif B.

AU - Rasheed, Suhail Ahmed Kabeer

AU - Mougiakakos, Dimitrios

AU - Oefner, Peter J.

AU - Sahin, Ozgur

AU - Volante, Marco

AU - Greten, Florian R.

AU - Brabletz, Thomas

AU - Ceppi, Paolo

PY - 2018/4

Y1 - 2018/4

N2 - Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 ( AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR.

AB - Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 ( AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR.

KW - A549 Cells

KW - Aldehyde Reductase/genetics

KW - Animals

KW - Cell Line, Tumor

KW - Colonic Neoplasms/pathology

KW - Epithelial-Mesenchymal Transition/genetics

KW - Glucose/metabolism

KW - HCT116 Cells

KW - HEK293 Cells

KW - HT29 Cells

KW - Humans

KW - L-Iditol 2-Dehydrogenase/genetics

KW - Lung Neoplasms/pathology

KW - MCF-7 Cells

KW - Mice

KW - RNA Interference

KW - RNA, Small Interfering/genetics

KW - Transforming Growth Factor beta/metabolism

U2 - 10.1158/0008-5472.CAN-17-2834

DO - 10.1158/0008-5472.CAN-17-2834

M3 - Journal article

C2 - 29343522

AN - SCOPUS:85047879742

SN - 0008-5472

VL - 78

SP - 1604

EP - 1618

JO - Cancer Research

JF - Cancer Research

IS - 7

ER -

Polyol pathway links glucose metabolism to the aggressiveness of cancer cells

Abstract

Keywords

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