Abstractp53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress. Inhibiting BTK reduced both p53-dependent senescence and apoptosis. Further, BTK expression also upregulated DNA damage signals and apoptosis. We conclude that despite being involved in oncogenic signals in blood malignancies, BTK has antineoplastic properties in other contexts, such as the enhancement of p53's tumor suppressor responses. Along with evidence that BTK expression correlates with good prognosis in some epithelial tumors, our findings may encourage a reevaluation of the clinical uses of BTK inhibitors in cancer therapy.
Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.
T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 370;3 nejm.org january 16, 2014 286 Efficacy of Vemurafenib in Hairy-Cell LeukemiaTo the Editor: The BRAF V600E mutation is present in nearly all cases of hairy-cell leukemia. 1 This finding has led to the introduction of BRAF inhibitors for the treatment of chemotherapy-resistant hairy-cell leukemia, and patients have had a good response to the oral inhibitor vemurafenib. 2-4 Constitutive phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated protein-ERK kinase (MEK) has been considered to be a direct consequence of BRAF activation, with BRAF inhibition resulting in cell death through suppression of this pathway in hairy-cell leukemia. However, data to support this theory are limited, since most patients present with pancytopenia.We evaluated a patient with purine analoguerefractory hairy-cell leukemia who had biallelic BRAF V600E mutations and a high leukemic burden during treatment with vemurafenib. Because of the high numbers of circulating hairy-cell leukemia cells, it was possible to study the effects of vemurafenib directly in vivo. Vemurafenib induced complete clinical remission with reduction of the viability of CD103+ hairy-cell leukemia cells during therapy (Fig. 1A). A pull-down and kinase assay showed inhibition of BRAF in leukemic cells in vivo (Fig. 1B). However, BRAF inhibition was not associated with any major changes in phosphorylation of either MEK or ERK in vivo, as shown by means of both immunoblot and flow cytometry (Fig. 1C), despite prolonged exposure to vemurafenib.Our experiments showed an unanticipated uncoupling between the decrease in BRAF activity (together with increased cell death) and MEK-ERK inhibition in vivo; this was not dependent on the duration of exposure to vemurafenib. We cannot rule out the possibility that BRAF inhibition in vivo eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood before leukemic cell death, but this possibility appears to be unlikely. First, our in vivo data clearly showed inhibition of BRAF without any change in phosphorylated ERK levels in leukemic cells, as shown by means of both immunoblot and flow cytometry, while cells were dying (as shown by the increasing level of propidium iodide staining). Second, the lack of effect of BRAF inhibitors on phosphorylated MEK and ERK was previously reproduced during prolonged incubation in vitro of hairycell leukemia cells obtained from the same patient, whereas the MEK 1 and MEK 2 inhibitor PD325901 successfully blocked ERK phosphorylation and induced significant cell death. 5 An alternative signaling pathway, as yet uncharacterized, may therefore be affected by vemurafenib, either directly or through BRAF inhibition, and it may have a strong impact in hairy-cell leukemia cell survival in vivo. These data have implications for the design of possible combination therapies. This 72-year-old man had had hairy-cell leukemia since he was 50 years of age. After ...
Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.
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