Abstract
Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by exposure to MSeA and selenite but not by SeM. They were accompanied by distinct anabolic dysregulation and reflected cell type-dependent changes in proliferation/death/cell cycle arrest. NSCLC OTC showed similar responses of PyC and/or glutaminolysis to the three agents, which correlated with tissue damages. Altogether, we found differential perturbations in anaplerosis-fueled anabolic pathways to underlie the distinct anti-cancer actions of the three Se agents, which could also explain the failure of SeM-based chemoprevention trials.
Document Type
Article
Publication Date
6-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/metabo13070774
Funding Information
This research was funded by National Institutes of Health, grant numbers 1P01CA163223- 01A1 (to ANL and TWMF), 1U24DK097215-01A1 (to RMH, TWMF, and ANL), 5R01 CA101199-02 to TWMF, 5R21ES025669-02 (to TWMF) and Edith D. Gardner (TWMF) and Carmen L. Buck (ANL) endowment funds. NMR and MS were recorded using the Metabolism Shared Resources supported in part by P30CA177558 (to B.M. Evers) and NIGMS COBRE 5P20GM121327 (to D. St. Clair).
Repository Citation
Fan, Teresa W-M; Winnike, Jason; Al-Attar, Ahmad; Belshoff, Alex C.; Lorkiewicz, Pawel; Tan, Jin Lian; Wu, Min; Higashi, Richard M.; and Lane, Andrew N., "Differential Inhibition of Anaplerotic Pyruvate Carboxylation and Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity of Selenium Agents in Human Lung Cancer" (2023). Markey Cancer Center Faculty Publications. 323.
https://uknowledge.uky.edu/markey_facpub/323
Included in
Biochemistry Commons, Endocrinology Commons, Molecular Biology Commons, Oncology Commons
Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).