Funded Grants

The Bcl2L12-microRNA-182 axis in glioblastoma

Malignant gliomas (MG) represent the most prevalent and lethal primary central nervous system cancer. Patients diagnosed with the highest grade MG, grade IV glioblastoma (GBM), survive for a mere 12-14 months after diagnosis despite aggressive surgical resection and treatment regimens. Multimodal approaches using radiation with concurrent chemotherapy (temozolomide) resulted in only a marginal increase in patients’ median survival. An incomplete understanding of how catalogued genetic aberrations dictate phenotypic hallmarks of the disease, particularly intense therapy (apoptosis) resistance, combined with a highly therapy-resistant cancer stem cell population (glioma stem cells, GSCs) have conspired to make GBM an enigmatic and incurable disease. The continued lack of success in treating high-grade gliomas with targeted (receptor) tyrosine kinase inhibitors, which have proven to be effective in other malignancies, has further underlined the overarching need to identify and dissect genetic aberrations in cell death pathways that play pivotal roles in the profound resistance to therapy exhibited by GBM. Consequently, three of the most fundamental questions in glioma research and drug development are: Can we identify anti-apoptotic mechanisms in GBM tumors that act as roadblocks for conventional and target therapies to induce tumor cell-specific apoptosis? How are these anti-apoptotic proteins regulated? And can we harness such information to neutralize their expression and function?

My laboratory has begun to address these questions on multiple levels. Recently, we discovered the unique Bcl-2 family protein Bcl2-Like 12 (Bcl2L12) as a novel anti-apoptotic glioma oncoprotein that targets key pathways important for gliomagenesis. Bcl2L12 exhibits robust overexpression in more than 90% of primary GBM tumors with low or undetectable levels in cells of glial origin in normal brain surrounding tumor tissue or in low-grade astrocytoma (1). Enforced expression of Bcl2L12 in primary cortical astrocytes enhanced cellular growth, conferred marked apoptosis resistance, yet engendered cellular necrosis and affected malignant transformation (1). RNAi-loss-of-function studies demonstrated that Bcl2L12 neutralization sensitizes glioma cells toward apoptosis, and most importantly, reduces intracranial tumor formation with increased (decreased) apoptotic (proliferative) indices and enhanced tumor-free survival (1). On the biochemical level, these oncogenic actions related significantly to the capacity of Bcl2L12 to inhibit apoptosis by neutralizing effector caspase-3 and -7 activity downstream of mitochondrial dysfunction and apoptosome activity (1, 2). Intriguingly, post-mitochondrial caspase activation acts as a molecular switch between apoptotic and necrotic cell death (3, 4): Due to mitochondrial dysfunction and cytochrome c release in the context of concomitantly neutralized effector caspase activation, oxidative phosphorylation and intracellular ATP levels decrease rendering cells unable to maintain ion homeostasis and provoking cellular edema, dissolution of organelles and plasma membranes. Indeed, Bcl2L12 expression promoted necrosis in response to apoptotic stimulation. In addition, Bcl2L12 physically interacts with and neutralizes the transactivational activity of the p53 tumor suppressor protein by abrogating p53 binding to its target gene promoters (5, 6). By blocking apoptosis and p53 signaling, and redirecting the death program to necrosis, the molecular profile of Bcl2L12 provides a rational molecular explanation for hallmark features of GBM