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Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors. (c) 2017 S. Karger AG, Basel
In the present study, we investigated the beneficial effects of trait self-compassion (SC) on perceived stress, shame, and the use of coping strategies in reaction to a socio-evaluative stressor while controlling for the effects of neuroticism (N) and conscientiousness (C). Participants (N = 105) performed a mental-arithmetic task with immediate in-person feedback. SC predicted less perceived stress and shame immediately after the stressor. Additionally, SC predicted less shame after a short recovery phase. This effect was fully mediated by less use of denial. Furthermore, SC buffered the effect of N on the use of denial, and C on shame after recovery. SC also predicted more use of positive reframing. Thus, SC may make a socio-evaluative stressor less threatening and may thwart a shame-inducing conception of the stressor by promoting clearer processing. Furthermore, SC may be especially beneficial for those vulnerable to dysfunctional coping and negative self-conscious emotions. This study contributes to the understanding of how trait self-compassion beneficially influences the processing of stressful situations.