Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation

M. Castells, D. Milhas, C. Gandy, B. Thibault, Arash Rafii Tabrizi, J. P. Delord, B. Couderc

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Epithelial ovarian carcinoma is characterized by high frequency of recurrence (70% of patients) and carboplatin resistance acquisition. Carcinoma-associated mesenchymal stem cells (CA-MSC) have been shown to induce ovarian cancer chemoresistance through trogocytosis. Here we examined CA-MSC properties to protect ovarian cancer cells from carboplatin-induced apoptosis. Apoptosis was determined by Propidium Iodide and Annexin-V-FITC labelling and poly- ADP-ribose polymerase cleavage analysis. We showed a significant increase of inhibitory concentration 50 and a 30% decrease of carboplatin-induced apoptosis in ovarian cancer cells incubated in the presence of CA-MSC-conditioned medium (CM). A molecular analysis of apoptosis signalling pathway in response to carboplatin revealed that the presence of CA-MSC CM induced a 30% decrease of effector caspases-3 and -7 activation and proteolysis activity. CA-MSC secretions promoted Akt and X-linked inhibitor of apoptosis protein (XIAP; caspase inhibitor from inhibitor of apoptosis protein (IAP) family) phosphorylation. XIAP depletion by siRNA strategy permitted to restore apoptosis in ovarian cancer cells stimulated by CA-MSC CM. The factors secreted by CA-MSC are able to confer chemoresistance to carboplatin in ovarian cancer cells through the inhibition of effector caspases activation and apoptosis blockade. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and the phosphorylation of its downstream target XIAP underlined the implication of this signalling pathway in ovarian cancer chemoresistance. This study reveals the potentialities of targeting XIAP in ovarian cancer therapy.

Original languageEnglish
Article numbere887
JournalCell Death and Disease
Volume4
Issue number10
DOIs
Publication statusPublished - Oct 2013
Externally publishedYes

Fingerprint

Cellular Microenvironment
Ovarian Neoplasms
Mesenchymal Stromal Cells
Carboplatin
Apoptosis
Carcinoma
Cell Line
Conditioned Culture Medium
Effector Caspases
X-Linked Inhibitor of Apoptosis Protein
Phosphorylation
Phosphatidylinositol 3-Kinase
Inhibitor of Apoptosis Proteins
Caspase 7
Caspase Inhibitors
Poly(ADP-ribose) Polymerases
Propidium
Fluorescein-5-isothiocyanate
Annexin A5
Caspase 3

Keywords

  • Chemoresistance
  • Mesenchymal stem cells
  • Microenvironment
  • Ovarian cancer
  • XIAP

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. / Castells, M.; Milhas, D.; Gandy, C.; Thibault, B.; Tabrizi, Arash Rafii; Delord, J. P.; Couderc, B.

In: Cell Death and Disease, Vol. 4, No. 10, e887, 10.2013.

Research output: Contribution to journalArticle

Castells, M. ; Milhas, D. ; Gandy, C. ; Thibault, B. ; Tabrizi, Arash Rafii ; Delord, J. P. ; Couderc, B. / Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. In: Cell Death and Disease. 2013 ; Vol. 4, No. 10.
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