RESUMEN
Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.
Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/metabolismo , MAP Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Neoplasias de la Mama Triple Negativas/metabolismo , Femenino , Humanos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 2/antagonistas & inhibidores , MAP Quinasa Quinasa 2/genética , MAP Quinasa Quinasa 5/antagonistas & inhibidores , MAP Quinasa Quinasa 5/genética , Células MCF-7 , Proteínas Proto-Oncogénicas c-fos/genética , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Light is a potent biologic force that profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in animals. Previously we examined the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit more light in the blue-appearing portion of the visible spectrum (465 to 485 nm) than do broad-spectrum cool white fluorescent (CWF) light, on the nighttime melatonin amplitude and circadian regulation of metabolism and physiology. In the current studies, we tested the hypothesis that exposure to blue-enriched LED light at day (bLAD), compared with CWF, promotes the circadian regulation of neuroendocrine, metabolic, and physiologic parameters that are associated with optimizing homeostatic regulation of health and wellbeing in 3 mouse strains commonly used in biomedical research (C3H [melatonin-producing], C57BL/6, and BALB/c [melatonin-non-producing]). Compared with male and female mice housed for 12 wk under 12:12-h light:dark (LD) cycles in CWF light, C3H mice in bLAD evinced 6-fold higher peak plasma melatonin levels at the middark phase; in addition, high melatonin levels were prolonged 2 to 3 h into the light phase. C57BL/6 and BALB/c strains did not produce nighttime pineal melatonin. Body growth rates; dietary and water intakes; circadian rhythms of arterial blood corticosterone, insulin, leptin, glucose, and lactic acid; pO2 and pCO2; fatty acids; and metabolic indicators (cAMP, DNA, tissue DNA 3H-thymidine incorporation, fat content) in major organ systems were significantly lower and activation of major metabolic signaling pathways (mTOR, GSK3ß, and SIRT1) in skeletal muscle and liver were higher only in C3H mice in bLAD compared with CWF. These data show that exposure of C3H mice to bLAD compared with CWF has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing that may influence scientific outcomes. The absence of enhancement in amelatonic strains suggests hyperproduction of nighttime melatonin may be a key component of the physiology.
Asunto(s)
Ritmo Circadiano/fisiología , Luz , Ratones Endogámicos BALB C/metabolismo , Ratones Endogámicos C3H/metabolismo , Ratones Endogámicos C57BL/metabolismo , Animales , Femenino , Masculino , Melatonina/sangre , Ratones/metabolismoRESUMEN
The aim of this study was to evaluate the anticancer and antitumor activities of ceramide analog 315 in nude mice. Nude mice (n=10) were injected bilaterally with 5×10 MDA-MB-231 cells on each side. Tumors were allowed to form for 2 weeks. The mice were then divided into two groups (n=5 in each group). The control group mice were injected with 25 µl of dimethyl sulfoxide and the treatment group mice were injected with 10 mg/kg of analog 315 (in dimethyl sulfoxide, 25 µl volume) every day for a period of 3 weeks. Animal weights and tumors were measured every week for 3 weeks. At the end of the experimental period, control animals had retained excess fluid, and showed larger tumor sizes compared with the treated group (2.95 vs. 1.67 g). A 45% reduction in tumor size and 80% decrease in tumor volume were observed in the treatment group. There was a significant increase in the weights of liver (10%) and spleen (19%) between the control and treated animals. Hematoxylin and Eosin staining of MDA-MB-231 tumor sections revealed more acellular necrotic regions in tumors from the treatment groups compared with the ones from the control group. Ki67, a proliferation marker was higher in number in control tumor section (71.8±12.8) compared to the treatment tumor section (37.4±10.4) (P<0.001). Photomicrographs showed metastatic tumor burden in kidney, lungs, and spleen collected from the control group mice bearing MDA-MB-231 tumors. Treatment group mice showed normal microscopic tissue architecture. Overall, our study showed tumor growth inhibition and antimetastatic effects for the novel ceramide analog 315.