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IKK-β mediates chemoresistance by sequestering FOXO3; a critical factor for cell survival and death

Tugsan Tezil1, Cagri Bodur, Ozgur Kutuk

  • 1Sabanci University, Biological Sciences and Bioengineering Program, 34956, Tuzla, Istanbul, Turkey. teziltugsan@su.sabanciuniv.edu

Cellular Signalling
|February 9, 2012
PubMed

Insights

FOXO3 enhances cisplatin sensitivity in breast cancer cells. Inhibitor IKK-beta blocks FOXO3, promoting chemoresistance by preventing nuclear localization and apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Chemotherapy resistance in breast cancer is a significant clinical challenge, often linked to cell-type-specific mechanisms.
  • The transcription factor FOXO3 regulates genes involved in cell death, but its precise role in chemoresistance remains unclear.

Purpose of the Study:

  • To investigate the role of FOXO3 in mediating cisplatin chemosensitivity in breast cancer.
  • To elucidate the mechanism by which IKK-beta influences FOXO3 activity and chemoresistance.

Main Methods:

  • Utilized MCF-7 (high FOXO3) and MDA-MB-231 (low FOXO3) breast cancer cell lines.
  • Employed RNA interference to assess FOXO3-dependent apoptosis induction by cisplatin.
  • Investigated the interaction between IKK-beta and FOXO3 using cisplatin treatment and overexpression models.

Main Results:

  • FOXO3 critically mediates cisplatin-induced apoptosis in MCF-7 cells.
  • IKK-beta inhibits FOXO3 nuclear localization and function in MDA-MB-231 cells, promoting chemoresistance.
  • Cisplatin treatment in FOXO3-overexpressing MDA-MB-231 cells led to autophagosome formation and inhibited caspase cleavage.

Conclusions:

  • FOXO3 levels and activity are crucial determinants of cisplatin chemosensitivity in breast cancer.
  • IKK-beta promotes chemoresistance by sequestering FOXO3 in the cytosol, hindering its pro-apoptotic function.

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