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Metabolic rewiring in drug resistant cells exhibit higher OXPHOS and fatty acids as preferred major source to

Sameer Salunkhe1, Saket V Mishra1, Atanu Ghorai2

  • 1Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India.

Biochimica Et Biophysica Acta. Bioenergetics
|August 29, 2020
PubMed

Insights

Drug-resistant leukemia cells shift metabolism from glucose to fatty acids. Targeting fatty acid oxidation and oxidative phosphorylation (OXPHOS) can re-sensitize these cancer cells to chemotherapy.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Metabolic Research

Background:

  • Metabolic alterations are linked to cancer drug resistance.
  • Targeting metabolic changes in resistant cancer cells remains a challenge.

Purpose of the Study:

  • To investigate the metabolic reprogramming in drug-resistant acute myeloid leukemia (AML) cells.
  • To identify novel therapeutic strategies targeting the metabolism of resistant AML.

Main Methods:

  • Comparative analysis of glucose and glutamine metabolism between sensitive and resistant AML cell lines.
  • Raman spectroscopy, electron microscopy, and lipid staining to assess cellular composition.
  • Gene set enrichment analysis to identify metabolic pathway alterations.
  • Assessment of mitochondrial activity, oxygen consumption, and fatty acid oxidation rates.
  • Evaluation of drug sensitivity upon inhibition of OXPHOS and fatty acid oxidation.

Main Results:

  • Drug-resistant HL-60/MX2 cells showed reduced aerobic glycolysis (Warburg effect) but maintained glutamine consumption.
  • Resistant cells exhibited increased lipid content, mitochondrial activity, and oxidative phosphorylation (OXPHOS).
  • Fatty acid metabolism was identified as a key energy source in resistant AML cells.
  • Inhibition of OXPHOS resensitized resistant cells to chemotherapy, while Etomoxir reduced their colony formation.

Conclusions:

  • Drug-resistant AML cells reprogram their metabolism towards fatty acid oxidation and OXPHOS for survival.
  • Targeting fatty acid metabolism and OXPHOS presents a promising strategy to overcome drug resistance in AML.
Keywords:
Drug resistanceLeukemiaLipid metabolismMitochondriaOXPHOS

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