Extracellular vesicle transmission of chemoresistance to ovarian cancer cells is associated with hypoxia-induced expression of glycolytic pathway proteins, and prediction of epithelial ovarian cancer disease recurrence

Mona Alharbi, Andrew Lai, Shayna Sharma, Priyakshi Kalita-De Croft, Nihar Godbole, America Campos, Dominic Guanzon, Alexis Salas-Burgos, Flavio Carrion, Felipe A. Zuñiga, Lewis Perrin, Yaowu He, Tanja Pejovic, Carmen Winters, Terry Morgan, John D. Hooper, Gregory E. Rice, Carlos Salomon

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.

Original languageEnglish (US)
Article number3388
JournalCancers
Volume13
Issue number14
DOIs
StatePublished - Jul 2 2021

Keywords

  • Exosomes
  • Extracellular vesicles
  • Hypoxia
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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