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Altered nuclear localization of bax protein in BCNU-resistant glioma cells
A Joy1, S Panicker, J R Shapiro
1Barrow Neurological Institute, Laboratory of Neuro-Oncology, Phoenix, AZ 85013, USA. ajoy@chw.edu
Abstract:
To investigate the role of apoptosis suppression in glioma chemotherapy resistance, protein levels and subcellular localization of bcl-2 family members were investigated in 2 pairs of sensitive cell lines and their in vitro generated resistant derivatives. The alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), induced apoptosis in both sensitive cell strains and apoptosis was suppressed in both resistant derivatives. Both resistant cell lines contained altered regulation of a bcl-2 related protein consistent with the suppression of apoptosis. Independent of which bcl-2 family member was dysregulated, resistance was associated with altered regulation in the subcellular localization of bax protein. Following BCNU treatment, bax accumulated in nucleoli and a nuclei containing fraction of sensitive cells but not their resistant derivatives. Nuclear accumulation was an early event in apoptosis induction. These data indicates altered subcellular localization of bax may play a role in resistance. In addition, the association between an early, nucleolar localization of bax and the induction of apoptosis suggests that localization of bax to nucleoli may play a role in apoptosis-induction of glioma cells.
Insights
Chemotherapy resistance in glioma involves suppressed apoptosis. Altered bax protein localization, particularly its nuclear accumulation, is linked to this resistance and may play a role in apoptosis induction.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Glioblastoma (glioma) is a highly aggressive brain tumor.
- Chemotherapy resistance is a major challenge in glioblastoma treatment.
- Apoptosis, or programmed cell death, is a key target for cancer therapies.
Purpose of the Study:
- To investigate the role of apoptosis suppression in glioblastoma chemotherapy resistance.
- To examine the protein levels and subcellular localization of bcl-2 family members in sensitive and resistant glioma cells.
- To determine the impact of the alkylating agent BCNU on apoptosis and bax protein localization.
Main Methods:
- Utilized two pairs of sensitive and in vitro generated resistant glioma cell lines.
- Analyzed protein levels and subcellular localization of bcl-2 family members.
- Treated cells with the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).
- Observed bax protein accumulation in nucleoli and nuclear fractions of sensitive cells post-BCNU treatment.
Main Results:
- BCNU induced apoptosis in sensitive glioma cells but was suppressed in resistant derivatives.
- Resistant cell lines showed altered regulation of bcl-2 related proteins, suppressing apoptosis.
- Resistance was associated with altered subcellular localization of bax protein.
- BCNU treatment led to bax accumulation in nucleoli and nuclear fractions of sensitive cells, but not resistant cells.
- Nuclear accumulation of bax was identified as an early event in apoptosis induction.
Conclusions:
- Altered subcellular localization of bax protein may contribute to glioblastoma chemotherapy resistance.
- The early nucleolar localization of bax is associated with apoptosis induction in glioma cells.
- Targeting bax localization could be a potential strategy to overcome chemotherapy resistance in glioblastoma.