BRCA1-IRIS overexpression promotes cisplatin resistance in ovarian cancer cells

Cancer Res. 2010 Nov 1;70(21):8782-91. doi: 10.1158/0008-5472.CAN-10-1352. Epub 2010 Oct 12.

Abstract

Evasion of apoptosis plays a key role in cancer development, drug resistance, and recurrence. The BRCA1 locus product protein BRCA1-IRIS is overexpressed in several cisplatin-resistant ovarian cancer cell lines, but its relationship to resistance is uncertain. Here, we show that in human ovarian surface epithelial (HOSE) cells, overexpression of BRCA1-IRIS triggers expression of the antiapoptotic protein survivin. Negative modulation of phosphatidylinositol 3-kinase (PI3K) signaling or AKT silencing reduced survivin expression in this setting. Conversely, silencing BRCA1-IRIS in ovarian cancer cell lines derepressed PTEN expression along with the antiapoptotic AKT targets FOXO1 and FOXO3a, suppressing survivin expression. Cisplatin (≤50 μmol/L) exposure was sufficient to activate expression of the BRCA1-IRIS-AKT-survivin cascade in HOSE cells, whereas under similar conditions cisplatin failed to induce apoptosis in ovarian cancer cell lines expressing this regulatory cascade. Mechanistic investigations indicated that BRCA1-IRIS triggers survivin expression through a PI3K/AKT-dependent pathway involving NF-κB, but also through a PI3K/AKT-independent pathway involving PTEN, FOXO1, and FOXO3a. Our findings indicate how BRCA1-IRIS overexpression prevents chemotherapy-induced cell death by upregulating expression of survivin, and they highlight this regulatory cascade as a candidate focus to improve treatment of advanced drug-resistant ovarian cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • BRCA1 Protein / antagonists & inhibitors
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Blotting, Western
  • Caspases / metabolism
  • Cell Cycle
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Female
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survivin

Substances

  • Antineoplastic Agents
  • BIRC5 protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • FOXO1 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B
  • RNA, Messenger
  • RNA, Small Interfering
  • Survivin
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Caspases
  • Cisplatin