Glioblastoma multiforme (GBM) is an invariably fatal malignancy. The lethality of GBM has been linked to the highly invasive nature of GBM cells, their escape from immune cell oversight and their high degree of resistance to multiple established therapeutic modalities. The resistance of GBM cells to undergo death processes has, in part, been associated with mutations of specific oncogenes and altered expression of other signaling molecules that lead to reduced capacities to activate multiple apoptosis pathways as well as altered rates of DNA repair and autophagy in response to cytotoxic drugs and cellular stresses. This review will examine how gene therapeutic approaches have been used in the past and are continuing to be used alongside cell signaling modulators and DNA damaging agents as clinical tools to treat GBM. The concerted use of established and novel signal transduction modulatory agents on GBM survival may have potential to lower the apoptotic threshold and facilitate killing in this lethal malignancy.

Background: ␤-Cell apoptosis, a critical contributor to T1D, involves iPLA 2 ␤ activation and is suppressed by Bcl-x(L). Results: iPLA 2 ␤-derived lipids activate an alternative 5Ј-splice site, reducing protective Bcl-x(L) protein. Conclusion:Modulation of Bcl-x splicing is another key mechanism by which iPLA 2 ␤-derived lipids promote ␤-cell apoptosis. Significance: Delineation of molecular mechanisms underlying iPLA 2 ␤-regulated splicing will elucidate novel strategies to counter ␤-cell death in T1D.

While breast cancer has an overall 5‐year survival rate of 90%, triple negative breast cancer (TNBC) represents an anomalous subset of the disease with a greatly reduced (30%) 5‐year survival rate. The enhanced mortality and morbidity associated with TNBC arises from the high metastatic rate, which requires the acquisition of anoikis resistance (AnR). As the dysregulation of mRNA splicing is becoming a recognized phenomenon in cancer and aberrant cell signaling, the alternative mRNA splicing events were interrogated in AnR TNBC cells using next generation sequencing. The mRNA splicing of cytoplasmic polyadenylation element binding 2 (CPEB2), a translational regulator, was identified as dysregulated in AnR TNBC. Specifically, the inclusion of exon 4 into the mature mRNA to produce high levels of the CEPB2B isoform correlated with AnR, which translated to human breast cancer tumors. Furthermore, the molecular manipulation of CPEB2 isoforms had a robust effect on AnR and the metastatic potential of TNBC. Finally, next generation sequencing indicated a subset of mRNA species related to both tumor suppression and oncogenesis were differentially regulated by specific CPEB2 splice variants. Overall, our findings demonstrate that the regulation of CPEB2 mRNA splicing is a key step in the acquisition of AnR for TNBC as well as a major driving force in metastasis.

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It recognized that agents that generate reactive oxygen species (ROS) enhance MDA-7/IL-24 lethality. The present studies focused on clarifying how such agents enhanced MDA-7/IL-24 toxicity in renal cell carcinoma cells (RCCs). Infection of RCCs with a tropism-modified serotype 5/3 adenovirus expressing MDA-7/IL-24, Ad.5/3-mda-7, caused plasma membrane clustering of CD95 and CD95 association with pro-caspase 8, effects that were enhanced by combined exposure to 17AAG, As2O3 or 4HPR, and which correlated with enhanced cell killing. Knock down of CD95 or expression of c-FLIP-s blocked enhanced killing. Inhibition of ROS generation, elevated cytosolic Ca2+, or de novo ceramide synthesis blocked Ad.5/3-mda-7 +/- agent-induced CD95 activation and the enhancement of apoptosis.Ad.5/3-mda-7-increased ceramide levels in a PERK-dependent fashion that were responsible for elevated cytosolic Ca2+ levels that promoted ROS generation; 17AAG did not further enhance cytokine-induced ceramide generation. In vivo, infection of RCC tumors with Ad.5/3-mda-7 suppressed the growth of infected tumors that was enhanced by exposure to 17AAG. Our data indicates that in RCCs Ad.5/3-mda-7-induced ceramide generation plays a central role in tumor cell killing and inhibition of multiple signaling pathways may have utility in promoting MDA-7/IL-24 lethality in renal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2011-5390