Global metabolic profile identifies choline kinase alpha as a key regulator of glutathione-dependent antioxidant cell defense in ovarian carcinoma

Anna Granata, Roberta Nicoletti, Paola Perego, Egidio Iorio, Balaji Krishnamachary, Fabio Benigni, Alessandro Ricci, Franca Podo, Zaver M. Bhujwalla, Silvana Canevari, Marina Bagnoli, Delia Mezzanzanica

Research output: Contribution to journalArticle

Abstract

Epithelial Ovarian Cancer (EOC) "cholinic phenotype", characterized by increased intracellular phosphocholine content sustained by over-expression/activity of choline kinase-alpha (ChoKα/CHKA), is a metabolic cellular reprogramming involved in chemoresistance with still unknown mechanisms. By stable CHKA silencing and global metabolic profiling here we demonstrate that CHKA knockdown hampers growth capability of EOC cell lines both in vitro and in xenotransplant in vivo models. It also affected antioxidant cellular defenses, decreasing glutathione and cysteine content while increasing intracellular levels of reactive oxygen species, overall sensitizing EOC cells to current chemotherapeutic regimens. Natural recovering of ChoKα expression after its transient silencing rescued the wild-type phenotype, restoring intracellular glutathione content and drug resistance. Rescue and phenocopy of siCHKA-related effects were also obtained by artificial modulation of glutathione levels. The direct relationship among CHKA expression, glutathione intracellular content and drug sensitivity was overall demonstrated in six different EOC cell lines but notably, siCHKA did not affect growth capability, glutathione metabolism and/or drug sensitivity of non-tumoral immortalized ovarian cells. The "cholinic phenotype", by recapitulating EOC addiction to glutathione content for the maintenance of the antioxidant defense, can be therefore considered a unique feature of cancer cells and a suitable target to improve chemotherapeutics efficacy.

Original languageEnglish
Pages (from-to)11216-11230
Number of pages15
JournalOncotarget
Volume6
Issue number13
Publication statusPublished - 2015

Keywords

  • Choline kinase
  • Glutathione
  • Ovarian cancer
  • Phosphocholine metabolism
  • Reversal of drug resistance

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Global metabolic profile identifies choline kinase alpha as a key regulator of glutathione-dependent antioxidant cell defense in ovarian carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Granata, A., Nicoletti, R., Perego, P., Iorio, E., Krishnamachary, B., Benigni, F., Ricci, A., Podo, F., Bhujwalla, Z. M., Canevari, S., Bagnoli, M., & Mezzanzanica, D. (2015). Global metabolic profile identifies choline kinase alpha as a key regulator of glutathione-dependent antioxidant cell defense in ovarian carcinoma. Oncotarget, 6(13), 11216-11230.