Sensitization of glioma cells by X-linked inhibitor of apoptosis protein knockdown
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Published on: November 28, 2015
Patricia L C Lopez1, Eduardo C Filippi-Chiela, Andrew O Silva
1Biophysics Department and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Objective:
Glioblastomas are a kind of cancer with high resistance to treatments, requiring more efficient alternatives of treatment. X-linked inhibitor of apoptosis (XIAP) is highly expressed in gliomas and, due to its inhibition of caspases, can participate in resistance to therapy. Here we test the sensitization of glioma cells with XIAP gene knockdown (KD) to drugs used in chemotherapy.
Methods:
We silenced XIAP expression in U87MG glioblastoma using stable shRNA, and cells were treated with taxol, BCNU, temozolomide, cisplatin, etoposide, resveratrol (Rsv), vincristine and doxorubicin. We analyzed cell viability, cell cycle, apoptosis and senescence.
Results:
XIAP KD cells were more sensitive to etoposide, Rsv, vincristine and doxorubicin compared to wild-type (WT) cells. Doxorubicin 1 µM and vincristine 100 nM induced higher activation of caspases after 24 h and doxorubicin induced a higher degree of senescence induction in XIAP KD cells in relation to WT cells. Phospho-p53 and phospho-H2Ax Western blot indicate subsequent DNA damage as an important effector of doxorubicin-induced death.
Conclusions:
This study suggests that XIAP inhibitors may sensitize gliomas to certain drugs and induce death and that the mechanisms of sensitization involve apoptosis, senescence and p53 signaling.
Insights
Reducing X-linked inhibitor of apoptosis (XIAP) enhances glioma cell sensitivity to chemotherapy drugs like doxorubicin and vincristine. This sensitization involves increased apoptosis, senescence, and DNA damage, offering potential new glioblastoma treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastomas exhibit high treatment resistance.
- X-linked inhibitor of apoptosis (XIAP) is overexpressed in gliomas and promotes therapy resistance by inhibiting caspases.
- Targeting XIAP may overcome glioblastoma treatment resistance.
Purpose of the Study:
- To investigate the potential of XIAP gene knockdown (KD) to sensitize glioma cells to standard chemotherapy agents.
- To explore the mechanisms underlying XIAP KD-mediated sensitization.
Main Methods:
- Stable XIAP knockdown was achieved in U87MG glioblastoma cells using shRNA.
- Cells were treated with various chemotherapeutic drugs including etoposide, doxorubicin, and vincristine.
- Cell viability, cell cycle progression, apoptosis, and senescence were analyzed.
Main Results:
- XIAP KD cells demonstrated increased sensitivity to etoposide, resveratrol, vincristine, and doxorubicin compared to wild-type cells.
- Doxorubicin and vincristine treatment led to higher caspase activation in XIAP KD cells.
- Doxorubicin induced greater senescence in XIAP KD cells, with evidence of DNA damage via p53 and H2Ax signaling.
Conclusions:
- XIAP inhibition can sensitize gliomas to specific chemotherapeutic drugs, potentially enhancing treatment efficacy.
- Mechanisms of sensitization include the induction of apoptosis, senescence, and activation of p53 signaling pathways.
- XIAP inhibitors represent a promising strategy for overcoming glioblastoma resistance.