title: RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines.
abstract: The RASSF1A tumor suppressor is potentially the most important candidate gene identified in medulloblastoma to date, being epigenetically silenced in >79% of primary tumors. However, its functional role has not been previously addressed in this tumor type. Here, we demonstrate that expression of RASSF1A promotes the induction of cell death after activation of both the extrinsic and intrinsic apoptotic pathways in medulloblastoma cells. Treatment of UW228-3 cells stably expressing RASSF1A with an anti-CD95 antibody to induce extrinsic apoptosis and etoposide or cisplatin to activate intrinsic apoptosis augmented tumor cell killing in a caspase-dependent manner. This led to increased activation of the pro-apoptotic BCL-2 family member BAX. On the basis of this knowledge, we demonstrate how the loss of RASSF1A function in medulloblastoma cells might be overcome using the novel BH3-only mimetic ABT-737 in combination with chemotherapeutic agents to target the BCL-2 anti-apoptotic members. We show that ABT-737 increased susceptibility to apoptosis induced by DNA damage regardless of RASSF1A expression status through increased activation of BAX. Our findings identify the RASSF1A tumor suppressor as a promoter of apoptotic signaling pathways. Investigation of its mechanism of action has revealed that these pathways can still be promoted in its absence and how these potentially represent novel therapeutic targets for medulloblastoma.
authors: Children's Brain Tumour Research Centre, Queen's Medical Centre, Medical School, Nottingham University, Nottingham NG7 2UH, UK.
authors: Jane
authors: J
authors: Levesley
authors: Meryl E
authors: ME
authors: Lusher
authors: Janet C
authors: JC
authors: Lindsey
authors: Steven C
authors: SC
authors: Clifford
authors: Richard
authors: R
authors: Grundy
authors: Beth
authors: B
authors: Coyle
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002648:Child; D002945:Cisplatin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; C411762:RASSF1 protein, human; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D020169:Caspases; D002945:Cisplatin