Differential Inhibition of Anaplerotic Pyruvate Carboxylation and Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity of Selenium Agents in Human Lung Cancer

Teresa W.M. Fan, Jason Winnike, Ahmad Al-Attar, Alexander C. Belshoff, Pawel K. Lorkiewicz, Jin Lian Tan, Min Wu, Richard M. Higashi, Andrew N. Lane

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number774
JournalMetabolites
Volume13
Issue number7
DOIs
StatePublished - Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • chemoprevention
  • glutaminolysis
  • methylseleninic acid
  • non-small cell lung cancer
  • pyruvate carboxylation
  • selenite
  • selenomethionine
  • stable isotope resolved metabolomics

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology

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