Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity
| Autor: | Morgan E. Collins, Frank H. Lau, Erik F. Flemington, Suzana D. Savkovic, Harrison M. Penrose, Rida Iftikhar, Alifiani B. Hartono, Sean Bong Lee, Angelle N. King, Susan E. Crawford, Melody Baddoo, Joshua S. Samudre |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Colorectal cancer business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Stem cells medicine.disease medicine.disease_cause Article digestive system diseases Transcriptome Cancer stem cell Lipid droplet Adipose triglyceride lipase medicine Cancer research Stem cell Carcinogenesis business Molecular Biology Reprogramming RC254-282 Cancer |
| Zdroj: | Oncogenesis Oncogenesis, Vol 10, Iss 11, Pp 1-10 (2021) |
| ISSN: | 2157-9024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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