Pharmacological reactivation of the p53 tumor suppressor is a promising strategy for anti-cancer therapy due to its high potential to elicit apoptosis or growth arrest in cancer cells. Recently we uncovered the mechanism of activation of the innate immune response by p53 upon its activation by small molecules.
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"This latter outcome is mediated by the upregulation of several proteins involved in the execution of cell death  , including the pro-apoptotic BCL-2 family members BAX and BBC3, the cytoplasmic adaptor APAF1 and the death receptor CD95 , as well as by transcription-independent mechanisms   . More recently, an intense wave of investigation has been centered on physiological aspects of the p53 biology, unveiling a key role for baseline p53 levels in the maintenance of energetic, redox, genomic and immune homeostasis   . Thus, p53 mediates oncosuppressive functions both as it contributes to the maintenance of intracellular homeostasis (de facto preventing malignant transformation), and as it directs the elimination of irremediably damaged (hence potentially tumorigenic) cells. "
[Show abstract][Hide abstract] ABSTRACT: Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors.
Seminars in Cancer Biology 05/2013; 23(5). DOI:10.1016/j.semcancer.2013.05.008 · 9.33 Impact Factor
"Because of the high potential of p53 to elicit apoptosis or growth arrest in cells, pharmacological reactivation of the p53 tumor suppressor is a promising strategy for anti-cancer therapy . Recently, proposed model suggested that p53 activation in vivo includes three major steps: (1) p53 stabilization, (2) release from MDM2 (i.e. "
[Show abstract][Hide abstract] ABSTRACT: Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.
PLoS ONE 12/2012; 7(12):e52162. DOI:10.1371/journal.pone.0052162 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is now clear that the immune system plays a critical role not only during oncogenesis and tumor progression, but also as established neoplastic lesions respond to therapy. Selected cytotoxic chemicals can indeed elicit immunogenic cell death, a functionally peculiar type of apoptosis that stimulates tumor-specific cognate immune responses. Such immunogenic chemotherapeutics include cyclophosphamide, doxorubicin and oxaliplatin (which are approved by FDA for the treatment of various hematological and solid malignancies), mitoxantrone (which is currently employed both as an anticancer agent and against multiple sclerosis) and patupilone (a microtubular poison in clinical development). One year ago, in the second issue of OncoImmunology, we discussed the scientific rationale behind immunogenic chemotherapy and reviewed the status of recent clinical trials investigating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone in cancer patients. Here, we summarize the latest developments in this area of clinical research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of immunogenic chemotherapeutics.