Resumen
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 CD133 HI 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.
Idioma original | English |
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Páginas (desde-hasta) | 2001-2017 |
Número de páginas | 17 |
Publicación | Clinical Cancer Research |
Volumen | 25 |
N.º | 6 |
DOI | |
Estado | Published - 2019 |
Nota bibliográfica
Funding Information:This work was supported by grants from the Canadian Institute of Health Research (CIHR) and from the Canadian Breast Cancer Foundation—Atlantic. T. Sharif was previously supported by a CIHR Postdoctoral Fellowship and is currently funded by the Cancer Research Training Program (CRTP) of the Beatrice Hunter Cancer Research Institute (BHCRI). C. Dai was supported by the Masters Fellowship from CIHR, whereas E. Martell is supported through Nova Scotia Graduate Scholarship and Nova Scotia Health Research Foundation Masters award. CRTP awards from the BHCRI have funded B.E. Kennedy, P.J. Murphy, and M.R. Hanes in the past. S. Gujar is supported by the Dalhousie Medical Research Foundation. The authors are grateful to Dr. Patrick Lee for his support of this study. The authors thank Drs. Devanand Pinto (National Research Council) and Alehandro Cohen (Dalhousie Proteomics Core) for their assistance with proteomics and metabolomics analysis.
Funding Information:
S.K. Singh is an employee of and has ownership interests (including patents) at Empirica Therapeutics, reports receiving speakers bureau honoraria from Amgen, is a consultant/advisory board member for Longbow Therapeutics, reports receiving commercial research grants from PTC Therapeutics, and reports receiving commercial research support from JanPix. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
ASJC Scopus Subject Areas
- Oncology
- Cancer Research