TAp73 modifies metabolism and positively regulates growth of cancer stem-like cells in a redox-sensitive manner

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 anti-cancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells have remained 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 (ECSLCs) as well as human breast cancer stem-like cells (BCSLCs). These findings were confirmed using patient-derived brain tumor-initiating cells (BTICs) 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 ROS through reduced 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 pro-survival factors Sox-2, BMI-1 and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability. Conclusion: Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming.

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