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The microenvironment plays an important role in regulating tumor response to radiotherapy. Ionizing radiation can disrupt tumor vasculature, and Notch pathway inhibition can interfere with functional angiogenesis. We explored the potential cooperativity between Notch inhibition and ionizing radiation in delaying tumor growth.

Stanley K Liu, Saif A S Bham, Emmanouil Fokas, John Beech, Jaehong Im, Song Cho, Adrian L Harris and Ruth J Muschel

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The activity of acid sphingomyelinase (aSMase) was previously reported to be involved in glucocorticoid-induced cell death (GICD) of T lymphocytes. This mechanism in turn is believed to contribute to the therapeutic efficacy of glucocorticoids (GCs) in the treatment of inflammatory diseases. In this study, we reassessed the role of aSMase in GICD by using aSMase knockout mice. The absence of aSMase largely abolished the partial protection that effector memory CD4+ T cells in wild-type mice possess against GICD. Reduced IL-2 secretion by aSMase-deficient CD4+ T cells suggested that a lack of this important survival factor might be the cause of these cells’ enhanced susceptibility to GICD. Indeed, addition of IL-2 restored the protection against GICD, whereas neutralization of IL-2 abrogated the otherwise protective effect seen in wild-type effector memory CD4+ T cells. The therapeutic implications of the altered sensitivity of aSMase-deficient T cells to GICD were assessed in models of inflammatory disorders; namely, experimental autoimmune encephalomyelitis and acute graft-versus-host disease. Surprisingly, GC treatment was equally efficient in both models in terms of ameliorating the diseases, regardless of the genotype of the T cells. Thus, our data reveal a hitherto unrecognized contribution of aSMase to the sensitivity of effector memory CD4+ T cells to GICD and call into question the traditionally attributed importance of GICD of T cells to the treatment of inflammatory diseases by GCs.

Denise Tischner, Jennifer Theiss, Anna Karabinskaya, Jens van den Brandt, Sybille D Reichardt, Ulrike Karow, Marco J Herold, Fred Lühder, Olaf Utermöhlen, and Holger M Reichardt

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Although caspase-2 represents the most conserved caspase across species and was the second caspase identified, its precise function remains enigmatic. In several cell types we show that knockdown of caspase-2 specifically impaired DNA damage-induced p21 expression, whereas overexpression of a caspase-2 mutant increased p21 levels. Caspase-2 did not influence p21 mRNA transcription; moreover, various inhibitors targeting proteasomal or non-proteasomal proteases, including caspases, could not restore p21 protein levels following knockdown of caspase-2. As, however, silencing of caspase-2 impaired exogenous expression of p21 constructs containing 3′-UTR sequences, our results strongly indicate that caspase-2 regulates p21 expression at the translational level. Intriguingly, unlike depletion of caspase-2, which prevented p21 expression and thereby reverted the γ-IR-induced senescent phenotype of wild-type HCT116 colon carcinoma cells into apoptosis, knockdown of none of the caspase-2-interacting components RAIDD, RIP or DNA-PKcs was able to mimic these processes. Together, our data suggest that this novel role of caspase-2 as a translational regulator of p21 expression occurs not only independently of its enzymatic activity but also does not require known caspase-2-activating platforms.

Academic paper: Caspase-2 is required for DNA damage-induced expression of the CDK inhibitor p21WAF1/CIP1. Available from: https://www.researchgate.net/publication/51034476_Caspase-2_is_required_for_DNA_damage-induced_expression_of_the_CDK_inhibitor_p21WAF1CIP1 [accessed May 2, 2017].

D Sohn, W Budach and R U Jänicke

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