TAp73 Modifies Metabolism and Positively Regulates Growth of Cancer Stem–Like Cells in a Redox-Sensitive Manner
| Autor: | Carman A. Giacomantonio, Mark Robert Hanes, Paola Marcato, Cathleen Dai, Barry E. Kennedy, Patrick J. Murphy, Chitra Venugopal, Shashi Gujar, Sheila K. Singh, Emma Martell, Minomi Subapanditha, Mohammad Saleh Ghassemi-Rad, Tanveer Sharif |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Homeobox protein NANOG Cancer Research Carcinogenesis Mice 03 medical and health sciences 0302 clinical medicine Neoplasms medicine Animals Humans Cell Self Renewal RNA Small Interfering Transcription factor Regulation of gene expression Gene knockdown Chemistry Cancer Tumor Protein p73 Cell cycle medicine.disease Xenograft Model Antitumor Assays Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer cell Neoplastic Stem Cells Commentary Female Stem cell Oxidation-Reduction |
| Zdroj: | Clinical Cancer Research. 25:2001-2017 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anticancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells remain unknown. Experimental Design: This study utilizes various in vitro molecular biology techniques, including immunoblotting, qRT-PCR, and mass spectrometry–based proteomics, and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLC) as well as human breast cancer stem-like cells (BCSLC). These findings were confirmed using patient-derived brain tumor–initiating cells (BTIC) and in vivo xenograft models. Results: TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog, and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo, TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT, and PYCR1 involved in the interconversion of proline–glutamine–ornithine. Further, TAp73 deficiency exacerbates glutamine dependency, enhances accumulation of reactive oxygen species through reduced superoxide dismutase 1 (SOD1) expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of prosurvival factors Sox-2, BMI-1, and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability. Conclusions: Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming. |
| Databáze: | OpenAIRE |
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