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Chemosensitivity linked to p73 function
Meredith S Irwin1, Keiichi Kondo, Maria Carmen Marin
1Dana-Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Most chemotherapeutic agents induce DNA damage, leading to p53 accumulation and apoptosis. The factors that determine chemosensitivity in p53-defective tumor cells are poorly understood. We found that the p53 family member p73 is induced by a wide variety of chemotherapeutic drugs. Blocking p73 function with a dominant-negative mutant, siRNA, or homologous recombination led to chemoresistance of human tumor cells and engineered transformed cells, irrespective of p53 status. Mutant p53 can inactivate p73 and downregulation of mutant p53 enhanced chemosensitivity. These findings indicate that p73 is a determinant of chemotherapeutic efficacy in humans.
Insights
The p53 family member p73 is crucial for chemotherapy effectiveness in human tumor cells, even those with defective p53. Blocking p73 function causes chemoresistance, highlighting its role in cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Chemotherapy typically induces DNA damage, leading to p53 activation and apoptosis.
- Understanding chemosensitivity in p53-defective tumors is critical for effective cancer treatment.
- The role of p53 family members in chemotherapy response remains incompletely understood.
Purpose of the Study:
- To investigate the role of the p53 family member p73 in determining chemotherapeutic efficacy.
- To explore the relationship between p73 function and chemoresistance in human tumor cells.
- To determine if p73 is a determinant of chemotherapy response, irrespective of p53 status.
Main Methods:
- Induction of p73 by various chemotherapeutic drugs was assessed.
- p73 function was blocked using dominant-negative mutants, siRNA, and homologous recombination.
- Chemoresistance was evaluated in human tumor cells and engineered transformed cells.
- The interaction between mutant p53 and p73 was investigated.
Main Results:
- The p53 family member p73 is induced by a broad spectrum of chemotherapeutic agents.
- Inhibition of p73 function resulted in chemoresistance in human tumor cells and engineered cells, independent of p53 status.
- Mutant p53 was found to inactivate p73.
- Downregulation of mutant p53 expression led to enhanced chemosensitivity.
Conclusions:
- p73 plays a significant role in mediating the response to chemotherapy.
- p73 is a key determinant of chemotherapeutic efficacy in human cancers.
- Targeting p73 may represent a novel strategy to overcome chemoresistance in tumors with defective p53.