iScience
Volume 26, Issue 2, 17 February 2023, 106045
Journal home page for iScience

Article
NRF3 activates mTORC1 arginine-dependently for cancer cell viability

https://doi.org/10.1016/j.isci.2023.106045Get rights and content
Under a Creative Commons license
open access

Highlights

  • NRF3 transcriptionally induces arginine-dependent mTORC1 recruitment onto lysosome

  • NRF3 enhances arginine loading via bulk macropinocytosis and selective transport

  • NRF3-mTORC1 axis contributes to mitochondrial quality control and cell viability

  • Aberrant upregulation of NRF3-mTORC1 axis causes tumor growth and poor prognosis

Summary

Cancer cells coordinate the mTORC1 signals and the related metabolic pathways to robustly and rapidly grow in response to nutrient conditions. Although a CNC-family transcription factor NRF3 promotes cancer development, the biological relevance between NRF3 function and mTORC1 signals in cancer cells remains unknown. Hence, we showed that NRF3 contributes to cancer cell viability through mTORC1 activation in response to amino acids, particularly arginine. NRF3 induced SLC38A9 and RagC expression for the arginine-dependent mTORC1 recruitment onto lysosomes, and it also enhanced RAB5-mediated bulk macropinocytosis and SLC7A1-mediated selective transport for arginine loading into lysosomes. Besides, the inhibition of the NRF3–mTORC1 axis impaired mitochondrial function, leading to cancer cell apoptosis. Consistently, the aberrant upregulation of the axis caused tumor growth and poor prognosis. In conclusion, this study sheds light on the unique function of NRF3 in arginine-dependent mTORC1 activation and the pathophysiological aspects of the NRF3–mTORC1 axis in cancer development.

Subject areas

Cellular physiology
Cell biology
Cancer

Data and code availability

The DNA microarray data have been deposited at NCBI’s Gene Expression Omnibus and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

6

Lead contact