Important Role of FTO in the Survival of Rare Panresistant Triple-Negative Inflammatory Breast Cancer Cells Facing a Severe Metabolic Challenge
| Autor: | Laura J. Washburn, Balraj Singh, Hannah E. Kinne, Mark Olsen, Ryan D. Milligan, Anthony Lucci |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology Glutamine Cancer Treatment lcsh:Medicine Gene Expression Triple Negative Breast Neoplasms Biochemistry Mice Drug Metabolism Gene expression Breast Tumors Medicine and Health Sciences Amino Acids lcsh:Science Protein Metabolism Multidisciplinary Organic Compounds Acidic Amino Acids Nuclear Proteins DNA-Binding Proteins Chemistry Physiological Parameters Oncology Physical Sciences Female Inflammatory Breast Neoplasms Research Article medicine.medical_specialty Cell Physiology Cell Survival Repressor Alpha-Ketoglutarate-Dependent Dioxygenase FTO Mice Nude Antineoplastic Agents Biology Inflammatory breast cancer 03 medical and health sciences Internal medicine Cell Line Tumor Breast Cancer medicine Genetics Animals Humans Pharmacokinetics Epigenetics Obesity Gene Homeodomain Proteins Pharmacology Cell growth lcsh:R Organic Chemistry Body Weight Chemical Compounds Biology and Life Sciences Proteins Cancers and Neoplasms Cell Biology medicine.disease Xenograft Model Antitumor Assays Cell Metabolism Repressor Proteins 030104 developmental biology Endocrinology Metabolism Cell culture Cancer research lcsh:Q Transcription Factors |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 7, p e0159072 (2016) |
| ISSN: | 1932-6203 |
| Popis: | We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells. The fat mass and obesity-associated protein FTO is overexpressed in MA cells. Obesity-associated cis-acting elements in non-coding region of FTO regulate the expression of IRX3 gene, thus activating obesity networks. Here we found that IRX3 protein is significantly overexpressed in MA cells (5 to 6-fold) as compared to the parental SUM149 cell line, supporting our hypothesis. We also obtained evidence that additional key regulators of energy balance such as ARID5B, IRX5, and CUX1 P200 repressor could potentially help progenitor-like TNBC cells survive in glutamine-free medium. MO-I-500, a pharmacological inhibitor of FTO, significantly (>90%) inhibited survival and/or colony formation of SUM149-MA cells as compared to untreated cells or those treated with a control compound MO-I-100. Curiously, MO-I-500 treatment also led to decreased levels of FTO and IRX3 proteins in the SUM149 cells initially surviving in glutamine-free medium as compared to MO-I-100 treatment. Interestingly, MO-I-500 treatment had a relatively little effect on cell growth of either the SUM149 or SUM149-MA cell line when added to a complete medium containing glutamine that does not pose a metabolic challenge. Importantly, once selected and cultured in glutamine-free medium, SUM149-MA cells were no longer affected by MO-I-500 even in Gln-free medium. We conclude that panresistant MA cells contain interconnected molecular networks that govern developmental status and energy balance, and genetic and epigenetic alterations that are selected during cancer evolution. |
| Databáze: | OpenAIRE |
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