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Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.

ABSTRACT: In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3?/?-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3?, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3? protein. Increased GSK3? expression stimulated the ?-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3?/?-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

SUBMITTER: Li Y

PROVIDER: S-EPMC6861228 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.

Li YongHao Y Liu Xiong X Lin Xian X Zhao Menyang M Xiao Yanyi Y Liu Chen C Liang Zixi Z Lin Zelong Z Yi Renhui R Tang Zibo Z Liu Jiahao J Li Xin X Jiang Qingping Q Li Libo L Xie Yinyin Y Liu Zhen Z Fang Weiyi W

Signal transduction and targeted therapy 20191118

In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3β/β-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epith ...[more]

PMID: 31754475

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Project description:Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30-50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1's role on p53 and PGC-1α with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10-9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.

Project description:IntroductionFemale sexual interest and arousal disorder is personally distressing for women. To better understand the mechanism of the candidate therapeutic, flibanserin, we determined its effects on an index of brain glucose metabolism.AimWe hypothesized that chronic treatment with flibanserin would alter metabolism in brain regions associated with serotonergic function and female sexual behavior.MethodsIn a crossover design, eight adult female common marmosets (Calithrix jacchus) received daily flibanserin or vehicle. After 7-12 weeks of treatment, the glucose metabolism radiotracer [(18) F]fluorodeoxyglucose (FDG) was administered to each female immediately prior to 30 minutes of interaction with her male pairmate, after which females were anesthetized and imaged by positron emission tomography. Whole-brain normalized images were analyzed with anatomically defined regions of interest. Whole-brain voxelwise mapping was used to explore treatment effects. Correlations were examined between alterations in metabolism and pairmate social grooming.Main outcome measuresChanges in metabolism associated with flibanserin were determined for dorsal raphe, medial prefrontal cortex (mPFC), medial preoptic area of hypothalamus (mPOA), ventromedial nucleus of hypothalamus, and field cornu ammonis 1 (CA1) of the hippocampus.ResultsIn response to chronic flibanserin, metabolism in mPOA declined, and this reduction correlated with increases in pairmate grooming. A cluster of voxels in frontal cortico-limbic regions exhibited reduced metabolism in response to flibanserin and overlapped with a voxel cluster in which reductions in metabolism correlated with increases in pairmate grooming. Finally, reductions in mPOA metabolism correlated with increases in metabolism in a cluster of voxels in somatosensory cortex.ConclusionsTaken together, these results suggest that flibanserin-induced reductions in female mPOA neural activity increase intimate affiliative behavior with male pairmates.

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Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.

Publications

Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.

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