Evaluation of the antitumor effects of the inhibition in vitro of the AP-1 transcription factor by DTCM-g in adult and pediatric glioblastoma

Abstract

Glioblastoma represents 50% of the brain tumor in adults; being less frequent in children (9%). Despite the therapeutic advances, the median survival of glioblastoma patients is still dismal, around one year. Treatment of this tumor is generally hampered by its invasive nature that leads to a high rate of recurrence after surgery, and its resistance to apoptosis and to conventional drugs. The transcription factor AP-1 is an important point of convergence of many pathways including proliferation, apoptosis and invasion. In glioblastomas, the c-Jun subunit of AP-1 is found hyperphosphorylated and therefore more active to act on gene transcription. In this situation, c-Jun develops an important role increasing the expression of several genes involved on cell proliferation, apoptosis and tumor invasion. Recently, a new specific AP-1 inhibitor called DTCM-g was synthesized. This inhibitor blocks the phosphorylation of c-Jun, preventing its translocation into the nucleus. DTCM-g has already shown antitumor activity in osteosarcoma and bladder cancer; however its potential antiproliferative effects in glioblastoma are still unknown. In view of this, this project aims to study the influence of AP-1 inhibition by DTCM-g on tumor growth and invasion in adult and pediatric glioblastoma cell lines, based on functional tests and on the expression dinamics of genes under its regulation.