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Molecular mechanisms of apoptosis activation by heat shock in multidrug-resistant Chinese hamster cells

Paulina K Wrzal1, Ahmed Bettaieb, Diana A Averill-Bates

  • 1Département des sciences biologiques, Université du Québec a Montréal, CP 8888, Succursale Centre Ville, Montréal, Québec H3C 3P8, Canada.

Radiation Research
|November 26, 2008
PubMed

Insights

Hyperthermia effectively induces apoptosis in multidrug-resistant (MDR) cancer cells by activating both death receptor and mitochondrial pathways. This suggests hyperthermia is a promising strategy for overcoming chemotherapy resistance in clinics.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Multidrug resistance (MDR) in cancer is a significant challenge, often linked to P-glycoprotein overexpression.
  • MDR cells can evade apoptosis, complicating chemotherapy efficacy.
  • Hyperthermia is a known sensitizer for radiation and chemotherapy.

Purpose of the Study:

  • To investigate hyperthermia's effects on apoptosis signaling pathways in MDR cells.
  • To compare apoptosis induction in MDR CHRC5 cells versus drug-sensitive AuxB1 cells.
  • To elucidate the molecular mechanisms of hyperthermia-induced apoptosis in P-glycoprotein-overexpressing MDR cells.

Main Methods:

  • Exposure of MDR CHRC5 and sensitive AuxB1 cells to hyperthermia (41-43°C).
  • Analysis of death receptor-mediated apoptosis pathway components (c-FLIP, caspase 8, caspase 10).
  • Assessment of mitochondria-mediated apoptosis pathway markers (Bax, tBid, mitochondrial membrane potential, Apaf-1, caspase 3).
  • Evaluation of clonogenic survival response to heat treatment.

Main Results:

  • MDR CHRC5 cells showed higher c-FLIP and lower caspase 8/10 activation via the death receptor pathway.
  • In the mitochondria pathway, CHRC5 cells exhibited increased Bax, tBid, mitochondrial depolarization, and Apaf-1.
  • Despite pathway differences, both cell types displayed similar caspase 3 activation and substrate cleavage.
  • Clonogenic survival assays revealed comparable responses to hyperthermia in both MDR and sensitive cells.

Conclusions:

  • Hyperthermia induces apoptosis in MDR cells through both death receptor and mitochondria-mediated pathways.
  • MDR cells exhibit distinct molecular responses to hyperthermia compared to sensitive cells, particularly in early signaling events.
  • Overall, MDR cells are not resistant to hyperthermia-induced apoptosis, and similar survival responses suggest its clinical potential.
  • Hyperthermia is a promising strategy for eradicating MDR tumor cells.

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