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Xu, Jingying; Ren, Xiuhai; Tran, Anthony; Erdreich-Epstein, Anat (2014)
Publisher: Oxford University Press
Languages: English
Types: Article
Subjects: Abstracts
BACKGROUND: Phosphotyrosine Interaction Domain containing protein-1 (PID1) was discovered in 2006. We recently showed that PID1 inhibits growth of brain tumor cell lines and its mRNA level is directly correlated with survival in glioma and medulloblastoma patients (Erdreich-Epstein et al, Clin Cancer Res). The growth-inhibitory effect of PID1 was due to decreased proliferation and increased cell death. METHODS/RESULTS: We hypothesized that PID1 sensitizes brain tumors to therapy, thus accounting for the longer survival in patients with higher PID1 mRNA. Indeed, while cisplatin (10 µg/ml) or transient PID1 overexpression each increased apoptosis of glioma and medulloblastoma cell lines, combining cisplatin with PID1 resulted in markedly higher apoptosis. Moreover, knockdown of PID1 by siRNA inhibited the cisplatin-induced mitochondrial membrane depolarization and apoptosis, suggesting that PID1 is partially required for cisplatin-induced apoptosis. Taken together, this suggests that PID1 sensitizes both glioma and medulloblastoma cell lines to cisplatin. Intriguingly, PID1 mRNA increased in response to chemotherapy in a time- and dose-dependent manner in brain tumor cell lines. The chemotherapy-induced increase in PID1 mRNA was blocked by inhibitors of NFkB, suggesting that regulation of PID1 mRNA increase may be an NF-kB-dependent process. Consistent with this, cisplatin increased activity of an NF-kB promoter reporter. Surprisingly, despite the chemotherapy-induced increase in PID1 mRNA, PID1 protein decreased in response to cisplatin, suggesting post-translational modification(s) of PID1 induced by cisplatin. Ongoing work is focusing on the mechanism and role of PID1 in response to chemotherapy, and examining the effect of PID1 on the response of tumors to chemotherapy in vivo. CONCLUSIONS: Our data show that PID1 sensitizes glioma and medulloblastoma cell lines to chemotherapy, possibly explaining the correlation between higher PID1 mRNA and longer patient survival. This suggests also that PID1 mimetics may act as chemotherapy sensitizers in brain tumor treatment.

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