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

Abstract 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 c...

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Autores principales:	Rida Iftikhar, Harrison M. Penrose, Angelle N. King, Joshua S. Samudre, Morgan E. Collins, Alifiani B. Hartono, Sean B. Lee, Frank Lau, Melody Baddoo, Erik F. Flemington, Susan E. Crawford, Suzana D. Savkovic
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/dad0fa3c4c914a0ebba7e45d5f2c7f93
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spelling	oai:doaj.org-article:dad0fa3c4c914a0ebba7e45d5f2c7f932021-12-05T12:10:54ZElevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity10.1038/s41389-021-00373-42157-9024https://doaj.org/article/dad0fa3c4c914a0ebba7e45d5f2c7f932021-11-01T00:00:00Zhttps://doi.org/10.1038/s41389-021-00373-4https://doaj.org/toc/2157-9024Abstract 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.Rida IftikharHarrison M. PenroseAngelle N. KingJoshua S. SamudreMorgan E. CollinsAlifiani B. HartonoSean B. LeeFrank LauMelody BaddooErik F. FlemingtonSusan E. CrawfordSuzana D. SavkovicNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncogenesis, Vol 10, Iss 11, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Rida Iftikhar Harrison M. Penrose Angelle N. King Joshua S. Samudre Morgan E. Collins Alifiani B. Hartono Sean B. Lee Frank Lau Melody Baddoo Erik F. Flemington Susan E. Crawford Suzana D. Savkovic Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
description	Abstract 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.
format	article
author	Rida Iftikhar Harrison M. Penrose Angelle N. King Joshua S. Samudre Morgan E. Collins Alifiani B. Hartono Sean B. Lee Frank Lau Melody Baddoo Erik F. Flemington Susan E. Crawford Suzana D. Savkovic
author_facet	Rida Iftikhar Harrison M. Penrose Angelle N. King Joshua S. Samudre Morgan E. Collins Alifiani B. Hartono Sean B. Lee Frank Lau Melody Baddoo Erik F. Flemington Susan E. Crawford Suzana D. Savkovic
author_sort	Rida Iftikhar
title	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_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_sort	elevated atgl in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/dad0fa3c4c914a0ebba7e45d5f2c7f93
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Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity

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