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Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

Lijun Shen1, Wing-Yan Au, Kai-Yau Wong

  • 1Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, People's Republic of China.

Molecular Cancer Therapeutics
|December 17, 2008
PubMed

Insights

Bortezomib induces cell death in natural killer (NK) lymphoma cells through apoptosis and mitotic catastrophe. Resistance to apoptosis can be overcome by higher bortezomib concentrations, activating mitotic catastrophe for potential cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Bortezomib (PS-341/Velcade) is a proteasome inhibitor used for multiple myeloma and mantle-cell lymphoma.
  • Previous research indicated bortezomib's therapeutic potential in natural killer (NK)-cell neoplasms.
  • Understanding bortezomib's mechanism of action in NK lymphoma is crucial for optimizing its use.

Purpose of the Study:

  • To investigate the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cells.
  • To compare the sensitivity of different NK lymphoma cell lines and primary cultures to bortezomib.
  • To identify alternative cell death pathways activated by bortezomib in resistant cells.

Main Methods:

  • Treatment of NK lymphoma cell lines (SNK-6, NK-YS) and primary NK lymphoma cultures with bortezomib.
  • Assessment of cell viability, apoptosis, cellular senescence, and cell cycle status.
  • Analysis of Bcl-2 family member turnover, M-phase arrest, cyclin B1 accumulation, and CDC2/CDK1 activity.

Main Results:

  • Bortezomib induced mitochondrial apoptosis in NK-YS and primary NK lymphoma cells at low concentrations.
  • SNK-6 cells exhibited resistance to apoptosis, requiring higher bortezomib concentrations (23 nmol/L) due to delayed Bcl-2 family member turnover.
  • At higher concentrations, bortezomib induced mitotic catastrophe in resistant SNK-6 cells, characterized by M-phase arrest and altered cell cycle regulation.

Conclusions:

  • Bortezomib induces cell death in NK lymphoma via both apoptosis and mitotic catastrophe.
  • Mitotic catastrophe serves as an alternative cell death mechanism in bortezomib-resistant NK lymphoma cells.
  • Targeting mitotic catastrophe with bortezomib may offer a novel therapeutic strategy for apoptosis-resistant NK-cell malignancies and other cancers.

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