ACLY facilitates colon cancer cell metastasis by CTNNB1

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Abstract

Background

Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear about the exact role of ACLY in the development of colon cancer metastasis.

Methods

To evaluate the role of ACLY in colon cancer metastasis, we performed cell migration and invasion assays in two ACLY-deficient colon cancer cell lines. Colon cancer mouse model is used to examine ACLY’s effects on colon metastasis potentials in vivo. We analyzed the correlation between ACLY and CTNNB1 protein in 78 colon cancer patients by Pearson correlation. To finally explore the relationship of ACLY and CTNNB1, we used western blots, migration and invasion assays to confirm that ACLY may regulate metastasis by CTNNB1.

Results

Our data showed that the abilities of cell migration and invasion were attenuated in ACLY-deficient HCT116 and RKO cell lines. Furthermore, we describe the mechanism of ACLY in promoting colon cancer metastasis in vitro and in vivo. ACLY could stabilize CTNNB1 (beta-catenin 1) protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, subsequently promote the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells. Immunohistochemical analysis of 78 colon cancer patients showed that the high expression levels of ACLY and CTNNB1 protein was positively correlated with metastasis of colon cancer.

Conclusions

These results shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy.

Electronic supplementary material

The online version of this article (10.1186/s13046-019-1391-9) contains supplementary material, which is available to authorized users.

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Most cited references 32

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FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling

Rudolf Zechner, Robert Zimmermann, Thomas O. Eichmann … (2012)

Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that “lipolytic signaling” is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.

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Wnt signaling in disease and in development.

Roel Nusse (2005)

The highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.

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De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

Evelien Rysman, Koen Brusselmans, Katryn Scheys … (2010)

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. ©2010 AACR.

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Author and article information

Contributors

Jun Wen: nyfcwenjun@163.com

Xuejie Min: minxuejie0915@126.com

Mengqin Shen: shenmengqin2013@126.com

Qian Hua: huaqian528@163.com

Yuan Han: hanyuan73@163.com

Li Zhao: 13524106958@126.com

Liu Liu: shadow_elve@sina.com

Gang Huang: huang2802@163.com

Jianjun Liu: lldq0406@126.com

Xiaoping Zhao: zxp0856@sina.com

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 12 September 2019

Publication date PMC-release: 12 September 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 401

Affiliations

[1 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, , Shanghai Jiao Tong University, ; Shanghai, China

[2 ]The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan Province China

[3 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Nuclear Medicine, Shanghai Chest Hospital, , Shanghai Jiao Tong University, ; Shanghai, China

[4 ]ISNI 0000 0001 2323 5732, GRID grid.39436.3b, Shanghai University of Medicine & Health Sciences, ; Shanghai, China

Article

Publisher ID: 1391

DOI: 10.1186/s13046-019-1391-9

PMC ID: 6740040

PubMed ID: 31511060

SO-VID: 3e819e77-1160-44ea-b46e-2ee9d899179a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 April 2019

Date accepted : 26 August 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81572719

Award ID: 81874202

Award ID: No.81530053

Award ID: 81602415

Award ID: No.81771858

Award Recipient : Liu Liu Jianjun Liu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acly,ctnnb1,colon cancer,metastasis,emt (epithelial-mesenchymal transition)

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acly, ctnnb1, colon cancer, metastasis, emt (epithelial-mesenchymal transition)

ACLY facilitates colon cancer cell metastasis by CTNNB1

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 32

FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling

Wnt signaling in disease and in development.

De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.

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