Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What’s more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2’s dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers

Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC

Role and regulation of FOXO3a: new insights into breast cancer therapy

Breast cancer is the most common malignancy in the world, particularly affecting female cancer patients. Enhancing the therapeutic strategies for breast cancer necessitates identifying molecular drug targets that effectively eliminate tumor cells. One of these prominent targets is the forkhead and O3a class (FOXO3a), a member of the forkhead transcription factor subfamily. FOXO3a plays a pivotal role in various cellular processes, including apoptosis, proliferation, cell cycle regulation, and drug resistance. It acts as a tumor suppressor in multiple cancer types, although its specific role in cancer remains unclear. Moreover, FOXO3a shows promise as a potential marker for tumor diagnosis and prognosis in breast cancer patients. In addition, it is actively influenced by common anti-breast cancer drugs like paclitaxel, simvastatin, and gefitinib. In breast cancer, the regulation of FOXO3a involves intricate networks, encompassing post-translational modification post-translational regulation by non-coding RNA (ncRNA) and protein-protein interaction. The specific mechanism of FOXO3a in breast cancer urgently requires further investigation. This review aims to systematically elucidate the role of FOXO3a in breast cancer. Additionally, it reviews the interaction of FOXO3a and its upstream and downstream signaling pathway-related molecules to uncover potential therapeutic drugs and related regulatory factors for breast cancer treatment by regulating FOXO3a

Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK

Background/Aims: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) is a novel tumor suppressor gene that is critical for regulating tumor cell invasion and metastasis. The expression of RECK is dramatically down-regulated in human cancers. Harmine, a tricyclic compound from Peganum harmala, has been shown to have potential anti-cancer activity. Methods: Cell proliferation assay (CCK-8 cell viability assay), cell cycle analysis (detection by flow cytometry), apoptosis staining assay (TUNEL staining), cell migration assay and invasion assay (transwell assay) were carried out to investigate the Harmine’s efficacy on non-small cell lung cancer (NSCLC) cells in vitro. A549-luciferase cell orthotropic transplantation xenograft mouse model was used to determine the effect of Harmine treatment on NSCLC in vivo. Western blotting analysis of cell growth and metastasis related signal pathways was conducted to investigate the molecular mechanism of Harmine’s inhibitory effect on NSCLC. Results: Harmine treatment effectively inhibited cell proliferation and induced the G1/S cell cycle arrest of NSCLC cells. Further study proved that Harmine treatment led to apoptosis induction. Furthermore, treatment with NSCLC cells with Hamine resulted in decreased cell migration and cell invasion in vitro. More importantly, Harmine treatment significantly suppressed the NSCLC tumor growth and metastasis in mouse xenograft model in vivo. Mechanistically, in Harmine-treated NSCLC cells, RECK expression and its downstream signaling cascade were dramatically activated. As a consequence, the expression level of MMP-9 and E-cadherin were significantly decreased. Conclusion: These findings identify Harmine as a promising activator of RECK signaling for metastatic NSCLC treatment

The influence of landscape alterations on changes in ground beetle (Carabidae) and spider (Araneae) functional groups between 1995 and 2013 in an urban fringe of China

International audienceUrbanization is one of the main causes of land use change, especially from 1990 to now in China, but knowledge of its effect on different functional groups of carabids and spiders in the adjacent rural areas over time remains limited. We assessed whether landscape alterations (1993 versus 2013) drove changes in carabid and spider functional groups (1995 versus 2013) in an agricultural landscape located on the fringe of a rapidly growing city in China. Although built-up land increased from 6.3% to 32% across the whole landscape, the overall species richness of carabids and spiders did not decline. In contrast to the reduction in species richness of large carabids, the species richness of small carabids increased. Species richness of both large and small spiders increased. The species composition of carabids and spiders significantly changed between 1995 and 2013. Species compositions of large, predatory carabids and large or ground-hunting spiders were more sensitive to the changes in built-up land than those of small, omnivorous carabids and small or web-building spiders. The amount of grassland (abandoned land covered by wild grass) also increased as farmers began to work in the city. The increased grassland significantly contributed to the increased species richness of predatory and macropterous carabids. However, increased landscape diversity did not affect species richness of either carabids or spiders. High landscape diversity was related to reduction in field size, resulting in a decrease in the mean body size of carabids. This indicates that evaluating the effect of landscape change on carabid and spider diversity should be based on their functional traits. Different taxa, even different functional groups, have different responses to landscape change. The increase in built-up land did not immediately reduce species richness at the urban fringe. Increasing wild grasslands and combining smaller fields may benefit farmland biodiversity in this region

Lycorine inhibits glioblastoma multiforme growth through EGFR suppression

Abstract Background Lycorine has been revealed to inhibit the development of many kinds of malignant tumors, including glioblastoma multiforme (GBM). Although compelling evidences demonstrated Lycorine’s inhibition on cancers through some peripheral mechanism, in-depth mechanism studies of Lycotine’s anti-GBM effects still call for further exploration. Epidermal Growth Factor Receptor (EGFR) gene amplification and mutations are the most common oncogenic events in GBM. Targeting EGFR by small molecular inhibitors is a rational strategy for GBM treatment. Methods The molecular docking modeling and in vitro EGFR kinase activity system were employed to identify the potential inhibitory effects of Lycorine on EGFR. And the Biacore assay was used to confirm the direct binding status between Lycorine and the intracellular EGFR (696–1022) domain. In vitro assays were conducted to test the suppression of Lycorine on the biological behavior of GBM cells. By RNA interference, EGFR expression was reduced then cells underwent proliferation assay to investigate whether Lycorine’s inhibition on GBM cells was EGFR-dependent or not. RT-PCR and western blotting analysis were carried out to investigate the underlined molecular mechanism that Lycorine exerted on EGFR itself and EGFR signaling pathway. Three different xenograft models (an U251-luc intracranially orthotopic transplantation model, an EGFR stably knockdown U251 subcutaneous xenograft model and a patient-derived xenograft model) were performed to verify Lycorine’s therapeutic potential on GBM in vivo. Results We identified a novel small natural molecule Lycorine binding to the intracellular EGFR (696–1022) domain as an inhibitor of EGFR. Lycorine decreased GBM cell proliferation, migration and colony formation by inducing cell apoptosis in an EGFR-mediated manner. Furthermore, Lycorine inhibited the xenograft tumor growths in three animal models in vivo. Besides, Lycorine impaired the phosphorylation of EGFR, AKT, which were mechanistically associated with expression alteration of a series of cell survival and death regulators and metastasis-related MMP9 protein. Conclusions Our findings identify Lycorine directly interacts with EGFR and inhibits EGFR activation. The most significant result is that Lycorine displays satisfactory therapeutic effect in our patient-derived GBM tumor xenograft, thus supporting the conclusion that Lycorine may be considered as a promising candidate in clinical therapy for GBM

Effect of present and past landscape structures on the species richness and composition of ground beetles (Coleoptera: Carabidae) and spiders (Araneae) in a dynamic landscape

Species diversity may have time-lagged responses to landscape changes, but whether species are more strongly related to present or past landscape could vary with the taxa or functional traits. In this study, the effects of present and past landscape structures on carabid and spider communities were investigated. We hypothesized that present landscape structure was more highly correlated to small, omnivorous or macropterous carabids and small or ground-hunting spiders, while past landscape structure was more highly correlated to large or predatory carabids and large spiders. We analyzed landscape data from 1955, 1977, 1984, 1993 and 2013 and species data from 1995 and 2013 within the suburb of Qianjiang, a city in China. We found that both past and present landscape metrics affected present species richness in 1995 and species composition in 2013 due to the correlation between past and present landscape metrics. The time delay or immediate response of species was species-specific and not dependent on different groups in relation to body size, wing morphology, dietary preference or foraging method. The stable landscape structure from 1984 to 1993 had the greatest impact on species richness in 1995. In addition, the semi-natural land without dramatic changes since 1977 significantly affected the carabid species diversity. In addition, the excessive increase in building lands from 1993 to 2013 also significantly affected species composition in 2013. Our studies suggested that both historical and present landscape structures, the magnitude of land use change and each species' traits should be the focus of biodiversity conservation activities