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Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity

Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer pat...

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Autores principales: Iftikhar, Rida, Penrose, Harrison M., King, Angelle N., Samudre, Joshua S., Collins, Morgan E., Hartono, Alifiani B., Lee, Sean B., Lau, Frank, Baddoo, Melody, Flemington, Erik F., Crawford, Susan E., Savkovic, Suzana D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630180/
https://www.ncbi.nlm.nih.gov/pubmed/34845203
http://dx.doi.org/10.1038/s41389-021-00373-4
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author Iftikhar, Rida
Penrose, Harrison M.
King, Angelle N.
Samudre, Joshua S.
Collins, Morgan E.
Hartono, Alifiani B.
Lee, Sean B.
Lau, Frank
Baddoo, Melody
Flemington, Erik F.
Crawford, Susan E.
Savkovic, Suzana D.
author_facet Iftikhar, Rida
Penrose, Harrison M.
King, Angelle N.
Samudre, Joshua S.
Collins, Morgan E.
Hartono, Alifiani B.
Lee, Sean B.
Lau, Frank
Baddoo, Melody
Flemington, Erik F.
Crawford, Susan E.
Savkovic, Suzana D.
author_sort Iftikhar, Rida
collection PubMed
description Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, and ABCC3) and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression.
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spelling pubmed-86301802021-12-01 Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity Iftikhar, Rida Penrose, Harrison M. King, Angelle N. Samudre, Joshua S. Collins, Morgan E. Hartono, Alifiani B. Lee, Sean B. Lau, Frank Baddoo, Melody Flemington, Erik F. Crawford, Susan E. Savkovic, Suzana D. Oncogenesis Article Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, and ABCC3) and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression. Nature Publishing Group UK 2021-11-29 /pmc/articles/PMC8630180/ /pubmed/34845203 http://dx.doi.org/10.1038/s41389-021-00373-4 Text en © The Author(s) 2021, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Iftikhar, Rida
Penrose, Harrison M.
King, Angelle N.
Samudre, Joshua S.
Collins, Morgan E.
Hartono, Alifiani B.
Lee, Sean B.
Lau, Frank
Baddoo, Melody
Flemington, Erik F.
Crawford, Susan E.
Savkovic, Suzana D.
Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title_full Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title_fullStr Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title_full_unstemmed Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title_short Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
title_sort elevated atgl in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630180/
https://www.ncbi.nlm.nih.gov/pubmed/34845203
http://dx.doi.org/10.1038/s41389-021-00373-4
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