Beyond effector caspase inhibition

Abstract

Malignant gliomas are the most common and lethal primary central nervous system cancer. Glioblastoma mutliforme (GBM), the most aggressive of these neoplasms, are generally lethal within 2 years of diagnosis due in part to the intense apoptosis resistance of its cancer cells, hence poor therapeutic response to conventional and targeted therapies.  Twenty years of research has uncovered key genetic events involved in disease initiation and progression, foremost the Tp53 tumor suppressor that is mutated or deleted in 35% of GBM. The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14^Arf (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4.  Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus.  In the cytoplasm, Bcl2L12 functions to inhibit caspases 3 and 7, in the nucleus, Bcl2L12 forms a complex with p53, modestly reduces p53 protein stability and prevents its binding to selected target gene promoter (e.g. p21, DR5, Noxa and PUMA), thereby inhibiting p53-directed transcriptomic changes upon DNA damage. Proteomic and multidimensional oncogenomic analyses confirmed a Bcl2L12-p53 signaling axis in GBM, as Bcl2L12 exhibited predominant genomic amplification, elevated mRNA and protein levels in GBM tumors with uncompromised p53 function. On the cell biological level, Bcl2L12 exerts robust inhibition of p53-dependent senescence and apoptosis processes in glioma cells. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of GBM.

Acknowledgements

A.H.S. was supported by NIH grant 5R00CA129172-04, a Zell and a Sidney Kimmel Scholar award. Grant support to R.A.D. derives from the Ben and Catherine Ivy Foundation, the Goldhirsh Foundation and NIH grant 5P01CA95616. R.A.D. is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. The results reviewed here are in part based upon data generated by The Cancer Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at cancergenome.nih.gov.

Figures and Tables

Figure 1 Nuclear and cytoplasmic anti-apoptotic activities of Bcl2L12. Bcl2L12 inhibits p53's transactivational activity and consequently abrogates transcription of selective cell cycle and apoptosis modulators, such as p21 and PUMA (left, nuclear, transcription-dependent functions). Bcl2L12's impact on p53-insigated autophagy, necrosis and metabolism-related pathways (representative targets highlighted in blue) require further studies. In the cytosol (right panel), p53 has direct apoptogenic activities at the level of mitochondria. Here, PUMA can displace p53 from an inhibitory p53:Bcl-x_L complex. Released p53 can act as a ‘BH3’-only activator of Bax/Bak to induce mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. Besides impacting p53, Bcl2L12 is a well-characterized inhibitor of postmitochondrial effector caspase activation, as it binds to and inhibits caspase-7 (Casp-7) and upregulates the small heat shock protein and caspase-3-specific inhibitor αB-crystallin (CRYAB). *, of note, Bcl2L12 selectively impacts p53 transcription and promoter occupancy.