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Cell fate after mitotic arrest in different tumor cells is determined by the balance between slippage and apoptotic

Patricia Galán-Malo1, Laura Vela, Oscar Gonzalo

  • 1Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain.

Toxicology and Applied Pharmacology
|December 20, 2011
PubMed

Insights

The Bcl-x(L)/Bak ratio and cyclin B1 degradation determine cancer cell fate after mitotic arrest. Vincristine treatment reveals varied responses, including apoptosis, mitotic slippage, and mitotic catastrophe, depending on these molecular factors.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Anti-mitotic drugs like vincristine induce tumor cell death, but the precise molecular pathways linking mitotic arrest to cell death remain unclear.
  • Understanding these pathways is crucial for developing effective cancer therapies that target cell division.

Purpose of the Study:

  • To investigate the molecular mechanisms governing cell fate decisions following mitotic arrest induced by the anti-mitotic drug vincristine.
  • To analyze how variations in Bcl-x(L)/Bak ratio and cyclin B1 degradation influence cell death pathways in different human tumor cell lines.

Main Methods:

  • Utilized vincristine, a microtubule-destabilizing drug, to induce mitotic arrest in various human tumor cell lines (Jurkat, RPMI 8226, HeLa, A549, MiaPaca2).
  • Manipulated gene expression, including Bcl-x(L) silencing and overexpression, and Bax/Bak silencing.
  • Employed proteasome inhibition to prevent cyclin B1 degradation.
  • Observed and analyzed cellular responses including apoptosis, mitotic slippage, endoreduplication, and mitotic catastrophe.

Main Results:

  • Different cell lines exhibited distinct responses to vincristine-induced mitotic arrest: apoptosis (Jurkat, RPMI 8226, HeLa), mitotic slippage followed by cell death (A549), and mitotic catastrophe (MiaPaca2).
  • Silencing Bcl-x(L) in A549 cells promoted apoptosis during mitotic arrest.
  • Overexpression of Bcl-x(L) or silencing Bax/Bak delayed apoptosis and promoted mitotic slippage/endoreduplication in Jurkat and RPMI 8226 cells.
  • Preventing cyclin B1 degradation in MiaPaca2 cells shifted cell death from mitotic catastrophe to apoptosis.
  • Mcl-1 provided limited protection, and its degradation was not essential for vincristine-induced cell death.

Conclusions:

  • The ratio of Bcl-x(L) to Bak is a key determinant of cell fate following mitotic arrest.
  • The capacity of tumor cells to degrade cyclin B1 significantly influences whether they undergo apoptosis or mitotic catastrophe.
  • These findings highlight the complex interplay of molecular factors that dictate cancer cell survival or death in response to anti-mitotic chemotherapy.

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