Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.

Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy

Ku80 cooperates with CBP to promote COX-2 expression and tumor growth.

Cyclooxygenase-2 (COX-2) plays an important role in lung cancer development and progression. Using streptavidin-agarose pulldown and proteomics assay, we identified and validated Ku80, a dimer of Ku participating in the repair of broken DNA double strands, as a new binding protein of the COX-2 gene promoter. Overexpression of Ku80 up-regulated COX-2 promoter activation and COX-2 expression in lung cancer cells. Silencing of Ku80 by siRNA down-regulated COX-2 expression and inhibited tumor cell growth in vitro and in a xenograft mouse model. Ku80 knockdown suppressed phosphorylation of ERK, resulting in an inactivation of the MAPK pathway. Moreover, CBP, a transcription co-activator, interacted with and acetylated Ku80 to co-regulate the activation of COX-2 promoter. Overexpression of CBP increased Ku80 acetylation, thereby promoting COX-2 expression and cell growth. Suppression of CBP by a CBP-specific inhibitor or siRNA inhibited COX-2 expression as well as tumor cell growth. Tissue microarray immunohistochemical analysis of lung adenocarcinomas revealed a strong positive correlation between levels of Ku80 and COX-2 and clinicopathologic variables. Overexpression of Ku80 was associated with poor prognosis in patients with lung cancers. We conclude that Ku80 promotes COX-2 expression and tumor growth and is a potential therapeutic target in lung cancer

State Control and the Effects of Foreign Relations on Bilateral Trade

Do states use trade to reward and punish partners? WTO rules and the pressures of globalization restrict states’ capacity to manipulate trade policies, but we argue that governments can link political goals with economic outcomes using less direct avenues of influence over firm behavior. Where governments intervene in markets, politicization of trade is likely to occur. In this paper, we examine one important form of government control: state ownership of firms. Taking China and India as examples, we use bilateral trade data by firm ownership type, as well as measures of bilateral political relations based on diplomatic events and UN voting to estimate the effect of political relations on import and export flows. Our results support the hypothesis that imports controlled by state-owned enterprises (SOEs) exhibit stronger responsiveness to political relations than imports controlled by private enterprises. A more nuanced picture emerges for exports; while India’s exports through SOEs are more responsive to political tensions than its flows through private entities, the opposite is true for China. This research holds broader implications for how we should think about the relationship between political and economic relations going forward, especially as a number of countries with partially state-controlled economies gain strength in the global economy

Supporting data for “The role of Wnt-β-catenin in cancer stemness and chemoresistance in three-dimensional cultures“

Three-dimensional (3D) culture is increasingly being recognized due to its superior capacity to simulate tissue-like structures compared with two-dimensional (2D) monolayers. Although much is known about the various characteristics of 2D and 3D cultures in certain cancer types, the knowledge on other tumor types is limited. In nasopharyngeal carcinoma (NPC), although Epstein-Barr virus (EBV) is consistently present in undifferentiated NPCs, most studies have focused on EBV-negative NPC cells. In Chapter 2, 3D spheroid models of EBV-positive NPC cells were developed and characterized, and they were compared with conventional 2D cultures, which showed different features of tumor phenotypes and treatment responses. In addition, RNA sequencing analysis indicated substantial transcriptomic differences between 3D spheroids and 2D monolayers. Specifically, Wnt/β-catenin and Eph/ephrin cell signaling pathways were discovered and recognized as activated signals in NPC spheroids as compared to 2D monolayers. United States Food and Drug Administration (FDA)-approved drugs targeting these signaling pathways involved in 3D spheroids can eliminate NPC cell growth/survival. These findings indicate the differential signaling in 3D NPC spheroids of potential therapeutic implications. Cisplatin and paclitaxel are the main chemotherapeutic agents used for the treatment of ovarian cancer. However, their effectiveness is limited due to inherent and acquired chemoresistance. Cancer stem cells (CSCs) are shown to be chemoresistant. In Chapter 3, a subpopulation of c-Kit (CD117)-positive CSCs was enriched under 3D stem cell-selective conditions to elucidate the critical transcriptional activators of CSCs. The CBP/β-catenin interaction plays a role in the maintenance of cancer stemness. Using coimmunoprecipitation on nuclear β-catenin followed by mass spectrometry analysis, SP100 and HRP2 were identified as novel transcription co-activators that bound β-catenin. SP100- and HRP2-β-catenin interactions were essential for the expansion and drug resistance of CSCs and correlated with poor clinical outcomes. These findings reveal novel interacting partners of β-catenin in cancer stemness and chemoresistance in ovarian cancer. Together, these findings provide a better understanding of 3D spheroids in NPC and ovarian cancer and demonstrate an essential role of Wnt/β-catenin signaling in these 3D cultures.</p

Transcriptome Response to Drought, Rehydration and Re-Dehydration in Potato

Potato is an important food crop and its production is susceptible to drought. Drought stress in crop growth is usually multiple- or long-term. In this study, the drought tolerant potato landrace Jancko Sisu Yari was treated with drought stress, rehydration and re-dehydration, and RNA-seq was applied to analyze the characteristics of gene regulation during these treatments. The results showed that drought-responsive genes mainly involved photosynthesis, signal transduction, lipid metabolism, sugar metabolism, wax synthesis, cell wall regulation, osmotic adjustment. Potato also can be recovered well in the re-emergence of water through gene regulation. The recovery of rehydration mainly related to patatin, lipid metabolism, sugar metabolism, flavonoids metabolism and detoxification besides the reverse expression of the most of drought-responsive genes. The previous drought stress can produce a positive responsive ability to the subsequent drought by drought hardening. Drought hardening was not only reflected in the drought-responsive genes related to the modified structure and cell components, but also in the hardening of gene expression or the &ldquo;memory&rdquo; of drought-responsive genes. Abundant genes involved photosynthesis, signal transduction, sugar metabolism, protease and protease inhibitors, flavonoids metabolism, transporters and transcription factors were subject to drought hardening or memorized drought in potato