PID1 increases chemotherapy-induced apoptosis in medulloblastoma and glioblastoma cells in a manner that involves NFκB

Phosphotyrosine Interaction Domain containing 1 (PID1; NYGGF4) inhibits growth of medulloblastoma, glioblastomaand atypical teratoid rhabdoid tumorcell lines. PID1 tumor mRNA levels are highly correlated with longer survival in medulloblastomaand glioma patients, suggesting their tumors may have been more sensitive to therapy. We hypothesized that PID1 sensitizes brain tumors to therapy. We found that PID1 increased the apoptosis induced by cisplatinand etoposidein medulloblastomaand glioblastomacell lines. PID1 siRNA diminished cisplatin-induced apoptosis, suggesting that PID1 is required for cisplatin-induced apoptosis. Etoposideand cisplatinincreased NFκB promoter reporter activity and etoposideinduced nuclear translocation of NFκB. Etoposidealso increased PID1 promoter reporter activity, PID1 mRNA, and PID1 protein, which were diminished by NFκB inhibitors JSH-23 and Bay117082. However, while cisplatinincreased PID1 mRNA, it decreased PID1 protein. This decrease in PID1 protein was mitigated by the proteasome inhibitor, bortezomib, suggesting that cisplatininduced proteasomedependent degradation of PID1. These data demonstrate for the first time that etoposide- and cisplatin-induced apoptosis in medulloblastomaand glioblastomacell lines is mediated in part by PID1, involves NFκB, and may be regulated by proteasomaldegradation. This suggests that PID1 may contribute to responsiveness to chemotherapy.