Abstract:
:Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase-specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ-induced G2/M-arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S-phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par-4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA-mediated par-4 phosphorylation that are important for par-4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle-dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc-dependent pathway to improve the efficacy of TMZ-based regimen for patients with gliomas.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Zhuang D,Liu Y,Mao Y,Gao L,Zhang H,Luan S,Huang F,Li Qdoi
10.1002/ijc.25985subject
Has Abstractpub_date
2012-01-15 00:00:00pages
309-18issue
2eissn
0020-7136issn
1097-0215journal_volume
130pub_type
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