RESUMEN
Retinoic acid (RA) displays potent anticarcinogenic activities that are mediated by the nuclear retinoic acid receptors (RARs). However, use of RA in oncology is limited by RA resistance acquired during carcinogenesis. Moreover, in some cancers, RA facilitates rather than inhibits growth. A clue to this paradoxical behavior was recently suggested by the findings that RA also activates PPARbeta/delta, a receptor involved in mitogenic and anti-apoptotic activities. The observations that partitioning of RA between its two receptors is regulated by two intracellular lipid-binding proteins-CRABP-II, which targets RA to RAR, and FABP5, which delivers it to PPARbeta/delta-further suggest that RA resistance may stem from the deregulation of the binding proteins, resulting in activation of PPARbeta/delta rather than RAR. Here, we show that, in the RA-resistant mouse model of breast cancer MMTV-neu, RA indeed activates the nonclassical RA receptor PPARbeta/delta. This behavior was traced to an aberrantly high intratumor FABP5/CRABP-II ratio. Decreasing this ratio in mammary tissue diverted RA from PPARbeta/delta to RAR and suppressed tumor growth. The data demonstrate the existence of a mechanism that underlies RA resistance in tumors, indicate that CRABP-II functions as a tumor suppressor, and suggest that the inhibition of FABP5 may comprise a therapeutic strategy for overcoming RA resistance in some tumors.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma/metabolismo , Resistencia a Antineoplásicos , Proteínas de Unión a Ácidos Grasos/metabolismo , Neoplasias Mamarias Animales/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Ácido Retinoico/agonistas , Tretinoina/farmacología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/antagonistas & inhibidores , PPAR delta/agonistas , PPAR-beta/agonistas , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
It has been shown that genetic inhibition of p53 leads to enhanced proliferation of hematopoietic stem cells (HSCs). This could, in theory, contribute to the increased frequency of tumor development observed in p53-deficient mice and humans. In our previous work, we identified chemical p53 inhibitors (PFTs) that suppress the transactivation function of p53 and protect cultured cells and mice from death induced by gamma irradiation (IR). Here we found that when applied to bone marrow cells in vitro or injected into mice, PFTb impeded IR-induced reduction of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) population sizes. In addition, we showed that PFTb stimulated HSC and HPC proliferation in the absence of IR in vitro and in vivo and mobilized HSCs to the peripheral blood. Importantly, however, PFTb treatment did not affect the timing or frequency of tumor development in irradiated p53 heterozygous mice used as a model for determination of carcinogenicity. Thus, although PFTb administration led to increased numbers of HSCs and HPCs, it was not carcinogenic in mice. These findings suggest that chemical p53 inhibitors may be clinically useful as safe and effective stimulators of hematopoiesis.
Asunto(s)
Benzotiazoles/farmacología , Células Madre Hematopoyéticas/citología , Neoplasias/patología , Tolueno/análogos & derivados , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Rayos gamma , Células Madre Hematopoyéticas/efectos de los fármacos , Ratones , Ratones Noqueados , Neoplasias/metabolismo , Tolueno/farmacologíaRESUMEN
The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by gamma- radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.
Asunto(s)
Envejecimiento/genética , Transformación Celular Neoplásica/genética , Trastornos Cronobiológicos/genética , Ritmo Circadiano/genética , Mutación/genética , Transactivadores/genética , Envejecimiento/metabolismo , Envejecimiento/efectos de la radiación , Envejecimiento Prematuro/genética , Envejecimiento Prematuro/metabolismo , Animales , Apoptosis/genética , Apoptosis/efectos de la radiación , Proteínas CLOCK , Proliferación Celular/efectos de la radiación , Transformación Celular Neoplásica/metabolismo , Trastornos Cronobiológicos/metabolismo , Trastornos Cronobiológicos/fisiopatología , Regulación hacia Abajo/genética , Regulación hacia Abajo/efectos de la radiación , Femenino , Rayos gamma/efectos adversos , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Predisposición Genética a la Enfermedad/genética , Inmunidad Innata/genética , Inmunidad Innata/efectos de la radiación , Tejido Linfoide/metabolismo , Tejido Linfoide/efectos de la radiación , Masculino , Ratones , FenotipoRESUMEN
In a small controlled study, clevudine, a potent inhibitor of hepadnaviruses, including hepatitis B virus and woodchuck hepatitis virus, suppressed hepatitis delta virus (HDV) viremia in chronically infected woodchucks. Suppression was correlated with the marked reduction of woodchuck hepatitis virus surface antigen in individual animals, consistent with the concept that repression of surface antigen expression may be a useful antiviral strategy for HDV.