Altered nuclear localization of bax protein in BCNU-resistant glioma cells

To investigate the role of apoptosis suppression in glioma chemotherapy res istance, protein levels and subcellular localization of bcl-2 family member s were investigated in 2 pairs of sensitive cell lines and their in vitro g enerated resistant derivatives. The alkylating agent, 1,3-bis(2-chloroethyl )-1-nitrosourea (BCNU), induced apoptosis in both sensitive cell strains an d apoptosis was suppressed in both resistant derivatives. Both resistant ce ll lines contained altered regulation of a bcl-2 related protein consistent with the suppression of apoptosis. Independent of which bcl-2 family membe r was dysregulated, resistance was associated with altered regulation in th e subcellular localization of bax protein. Following BCNU treatment, bax ac cumulated in nucleoli and a nuclei containing fraction of sensitive cells b ut not their resistant derivatives. Nuclear accumulation was an early event in apotosis induction. These data indicates altered subcellular localizati on of bax may play a role in resistance. In addition, the association betwe en an early, nucleolar localization of bax and the induction of apoptosis s uggests that localization of bax to nucleoli may play a role in apoptosis-i nduction of glioma cells.