Upregulation of mitochondrial NADlevels impairs the clonogenicity of SSEA1glioblastoma tumor-initiating cells.

in Experimental & molecular medicine by Myung Jin Son, Jae-Sung Ryu, Jae Yun Kim, Youjeong Kwon, Kyung-Sook Chung, Seon Ju Mun, Yee Sook Cho

TLDR

  • The study found that increasing the levels of a molecule called NAD in the mitochondria of cancer cells called TICs made them less able to form spheres and more likely to differentiate, which means they lost some of their cancer-like properties. Conversely, reducing the levels of NAD made the TICs more likely to keep their cancer-like properties. The study also found that increasing the levels of a protein called SIRT3 and reducing the levels of a molecule called lactate made the TICs more like healthy cells. The findings suggest that targeting the mitochondria of cancer cells with NAD and SIRT3 could be a new way to treat cancer.

Abstract

Emerging evidence has emphasized the importance of cancer therapies targeting an abnormal metabolic state of tumor-initiating cells (TICs) in which they retain stem cell-like phenotypes and nicotinamide adenine dinucleotide (NAD) metabolism. However, the functional role of NADmetabolism in regulating the characteristics of TICs is not known. In this study, we provide evidence that the mitochondrial NADlevels affect the characteristics of glioma-driven SSEA1TICs, including clonogenic growth potential. An increase in the mitochondrial NADlevels by the overexpression of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT) significantly suppressed the sphere-forming ability and induced differentiation of TICs, suggesting a loss of the characteristics of TICs. In addition, increased SIRT3 activity and reduced lactate production, which are mainly observed in healthy and young cells, appeared following NNT-overexpressed TICs. Moreover, in vivo tumorigenic potential was substantially abolished by NNT overexpression. Conversely, the short interfering RNA-mediated knockdown of NNT facilitated the maintenance of TIC characteristics, as evidenced by the increased numbers of large tumor spheres and in vivo tumorigenic potential. Our results demonstrated that targeting the maintenance of healthy mitochondria with increased mitochondrial NADlevels and SIRT3 activity could be a promising strategy for abolishing the development of TICs as a new therapeutic approach to treating aging-associated tumors.

Overview

  • The study investigates the role of mitochondrial NAD levels in regulating the characteristics of glioma-driven SSEA1TICs, including clonogenic growth potential. The study uses the overexpression of the mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT) to increase mitochondrial NAD levels and assesses the effects on TIC characteristics, sphere-forming ability, differentiation, SIRT3 activity, and lactate production. The study aims to determine whether targeting the maintenance of healthy mitochondria with increased mitochondrial NAD levels and SIRT3 activity could be a promising strategy for abolishing the development of TICs as a new therapeutic approach to treating aging-associated tumors.

Comparative Analysis & Findings

  • The study found that an increase in mitochondrial NAD levels by NNT overexpression significantly suppressed the sphere-forming ability and induced differentiation of TICs, suggesting a loss of the characteristics of TICs. Conversely, the short interfering RNA-mediated knockdown of NNT facilitated the maintenance of TIC characteristics, as evidenced by the increased numbers of large tumor spheres and in vivo tumorigenic potential. The study also found increased SIRT3 activity and reduced lactate production following NNT-overexpressed TICs, which are mainly observed in healthy and young cells. In vivo tumorigenic potential was substantially abolished by NNT overexpression.

Implications and Future Directions

  • The study's findings suggest that targeting the maintenance of healthy mitochondria with increased mitochondrial NAD levels and SIRT3 activity could be a promising strategy for abolishing the development of TICs as a new therapeutic approach to treating aging-associated tumors. Future research could further explore the mechanisms underlying the effects of mitochondrial NAD levels on TIC characteristics and investigate the potential of this approach in clinical settings. Limitations of the study include the use of a specific cell line and the need for further validation in animal models and human samples.
Read Full Article