Altered nuclear localization of bax protein in BCNU-resistant glioma cells.
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.
Joy
A
A
Barrow Neurological Institute, Laboratory of Neuro-Oncology, Phoenix, AZ 85013, USA. ajoy@chw.edu
Panicker
S
S
Shapiro
J R
JR
D017304:Annexin A5 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002330:Carmustine / Q000494:pharmacology*; D002466:Cell Nucleolus / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism; D009697:Nucleolus Organizer Region / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D017304:Annexin A5; D018906:Antineoplastic Agents, Alkylating; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins; D002330:Carmustine