Lipid accumulation in human breast cancer cells injured by iron depletors

Maida De Bortoli, Elena Taverna, Elisa Maffioli, Patrizia Casalini, Francesco Crisafi, Vikas Kumar, Claudio Caccia, Dario Polli, Gabriella Tedeschi, Italia Bongarzone

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Current insights into the effects of iron deficiency in tumour cells are not commensurate with the importance of iron in cell metabolism. Studies have predominantly focused on the effects of oxygen or glucose scarcity in tumour cells, while attributing insufficient emphasis to the inadequate supply of iron in hypoxic regions. Cellular responses to iron deficiency and hypoxia are interlinked and may strongly affect tumour metabolism. Methods: We examined the morphological, proteomic, and metabolic effects induced by two iron chelators-deferoxamine (DFO) and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)-on MDA-MB-231 and MDA-MB-157 breast cancer cells. Results: These chelators induced a cytoplasmic massive vacuolation and accumulation of lipid droplets (LDs), eventually followed by implosive, non-autophagic, and non-apoptotic death similar to methuosis. Vacuoles and LDs are generated by expansion of the endoplasmic reticulum (ER) based on extracellular fluid import, which includes unsaturated fatty acids that accumulate in LDs. Typical physiological phenomena associated with hypoxia are observed, such as inhibition of translation, mitochondrial dysfunction, and metabolic remodelling. These survival-oriented changes are associated with a greater expression of epithelial/mesenchymal transcription markers. Conclusions: Iron starvation induces a hypoxia-like program able to scavenge nutrients from the extracellular environment, and cells assume a hypertrophic phenotype. Such survival strategy is accompanied by the ER-dependent massive cytoplasmic vacuolization, mitochondrial dysfunctions, and LD accumulation and then evolves into cell death. LDs containing a greater proportion of unsaturated lipids are released as a consequence of cell death. The consequence of the disruption of iron metabolism in tumour tissue and the effects of LDs on intercellular communication, cancer-inflammation axis, and immunity remain to be explored. Considering the potential benefits, these are crucial subjects for future mechanistic and clinical studies.

Original languageEnglish
Article number75
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
Publication statusPublished - Apr 3 2018

Keywords

  • Breast cancer
  • cytoplasm vacuolation
  • endoplasmic reticulum stress
  • hypoxia
  • iron chelation
  • lipid droplets
  • macropinocytosis
  • methuotic cell death
  • mitochondria dysfunctions
  • Raman spectroscopy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Lipid accumulation in human breast cancer cells injured by iron depletors'. Together they form a unique fingerprint.

Cite this