Effects of Isoxazolyl Steroids on Key Genes of Sonic Hedgehog Cascade Expression in Tumor Cells.

Activation of the Hedgehog (Hh) signaling pathway is often associated with the progression of various types of cancer. The purpose of study was to search for inhibitors of the Hh signaling pathway among eight compounds belonging to the group of isoxazolyl steroids. The evaluation of the effectiveness of the compounds was based on the analysis of their cytotoxicity, effect on the cell cycle, on the expression of key Hh-signaling-pathway genes (Ptch1, Smo, and Gli1) and putative target genes MMP-2 and MMP-9. Four compounds with the most pronounced cytotoxic effect were identified: compounds 1, 2 (HeLa cells) and 3, 4 (A549 cells). Compounds 1 and 2 significantly reduced the expression of the Ptch1, Smo, Gli1 genes, but had the opposite effect on MMP-2 gene expression: Compound 1 increased it, and compound 2 decreased it. Compounds 3 and 4 did not have a noticeable inhibitory effect on the expression of the Shh pathway receptors, but significantly inhibited MMP-2 and MMP-9 expression. Thus, it was shown that inhibition of the Shh signaling pathway by isoxazolyl steroids can have the opposite effect on MMPs gene expression, which is what should be taken into account in further studies of these compounds as therapeutic agents.

Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.

Cancer cell clusters have a higher capacity for metastasis than single cells, suggesting cancer cell clusters have biological properties different from those of single cells. The nature of de novo cancer cell clusters that are newly formed from tumor masses is largely unknown. Herein, we generated small cell clusters from colorectal cancer organoids and tracked the growth patterns of the clusters up to four cells. Growth patterns were classified into actively growing and poorly growing spheroids (PG). Notch signaling was robustly activated in small clusters immediately after dissociation, and Notch signaling inhibition markedly increased the proportion of PG spheroids. Only a limited number of PG spheroids grew under growth-permissive conditions in vitro, but xenograft tumors derived from Notch inhibited clusters showed growth rates comparable to those of untreated spheroids. Thus, de novo clusters are composed of cells with interchangeable growth fates, which are regulated in a context-dependent manner by Notch signaling.

Dormancy and awakening of cancer cells: the extracellular vesicle-mediated cross-talk between Dr. Jekill and Mr. Hyde.

Cancer cell dormancy is a reversible process whereby cancer cells enter a quiescent state characterized by cell cycle arrest, inhibition of cell migration and invasion, and increased chemoresistance. Because of its reversibility and resistance to treatment, dormancy is a key process to study, monitor, and interfere with, in order to prevent tumor recurrence and metastasis and improve the prognosis of cancer patients. However, to achieve this goal, further studies are needed to elucidate the mechanisms underlying this complex and dynamic dual process. Here, we review the contribution of extracellular vesicles (EVs) to the regulation of cancer cell dormancy/awakening, focusing on the cross-talk between tumor and non-tumor cells in both the primary tumor and the (pre-)metastatic niche. Although EVs are recognized as key players in tumor progression and metastasis, as well as in tumor diagnostics and therapeutics, their role specifically in dormancy induction/escape is still largely elusive. We report on the most recent and promising results on this topic, focusing on the EV-associated nucleic acids involved. We highlight how EV studies could greatly contribute to the identification of dormancy signaling pathways and a dormancy/early awakening signature for the development of successful diagnostic/prognostic and therapeutic approaches.

LSD1 is a promising target to treat cancers by modulating cell stemness.

As the first discovered histone demethylase, LSD1 plays a vital role in maintaining pathological processes such as cancer, infection, and immune diseases. Based on previous researches, LSD1 is highly expressed in sorts of tumor cells such as acute myeloid leukemia, non-small cell lung cancer, prostate cancer, breast cancer and gastric cancer, etc. Therefore, targeting LSD1 is a prospective strategy for tumor treatment. Cancer stem cells could preserve self-renewal, cell proliferation, cell migration and malignant phenotype. So, the reduction of tumor cell stemness can effectively inhibit the growth of tumor cells, which may be a new strategy for the treatment of cancers. Up to now, there exist many researches confirming the significant role of LSD1 in regulating the stemness characteristics such as embryonic stem cells differentiation. Many reports show that inhibition of LSD1 effectively decreases the property of cancer cell stemness. However, there lacks a detailed review about the relationship between LSD1 and cancer cell stemness. Herein, in this review, we summarized the mechanisms how LSD1 regulates cell stemness comprehensively. In addition, some related inhibitors targeting LSD1 to reduce the proliferation characteristics of cancer stem cells are also described.

MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer.

Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.

m6A-modified cenRNA stabilizes CENPA to ensure centromere integrity in cancer cells.

m6A modification is best known for its critical role in controlling multiple post-transcriptional processes of the mRNAs. Here, we discovered elevated levels of m6A modification on centromeric RNA (cenRNA) in cancerous cells compared with non-cancerous cells. We then identified CENPA, an H3 variant, as an m6A reader of cenRNA. CENPA is localized at centromeres and is essential in preserving centromere integrity and function during mitosis. The m6A-modified cenRNA stabilizes centromeric localization of CENPA in cancer cells during the S phase of the cell cycle. Mutations of CENPA at the Leu61 and the Arg63 or removal of cenRNA m6A modification lead to loss of centromere-bound CENPA during S phase. This in turn results in compromised centromere integrity and abnormal chromosome separation and hinders cancer cell proliferation and tumor growth. Our findings unveil an m6A reading mechanism by CENPA that epigenetically governs centromere integrity in cancer cells, providing potential targets for cancer therapy.

New players in the landscape of renal cell carcinoma bone metastasis and therapeutic opportunities.

Approximately one-third of advanced renal cell carcinoma (RCC) patients develop osteolytic bone metastases, leading to skeletal complications. In this review, we first provide a comprehensive perspective of seminal studies on bone metastasis of RCC describing the main molecular modulators and growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction. We next focus on newer developments revealing with in-depth details, the bidirectional interplay between renal cancer cells and the immune and stromal microenvironment that can through epigenetic reprogramming, profoundly affect the behaviors of transformed cells. Understanding their mechanistic interactions is of paramount importance for advancing both fundamental and translational research. These new investigations into the landscape of RCC-bone metastasis offer novel insights and identify potential avenues for future therapeutic interventions.

Single Cell Droplet-Based Efficacy and Transcriptomic Analysis of a Novel Anti-KLRG1 Antibody for Elimination of Autoreactive T Cells.

Progress in developing improvements in the treatment of autoimmune disease has been gradual, due to challenges presented by the nature of these conditions. Namely, the need to suppress a patient's immune response while maintaining the essential activity of the immune system in controlling disease. Targeted treatments to eliminate the autoreactive immune cells driving disease symptoms present a promising new option for major improvements in treatment efficacy and side effect management. Monoclonal antibody therapies can be applied to target autoreactive immune cells if the cells possess unique surface marker expression patterns. Killer cell lectin like receptor G1 (KLRG1) expression on autoreactive T cells presents an optimal target for this type of cell depleting antibody therapy. In this study, we apply a variety of in vitro screening methods to determine the efficacy of a novel anti-KLRG1 antibody at mediating specific natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC). The methods include single-cell droplet microfluidic techniques, allowing timelapse imaging and sorting based on cellular interactions. Included in this study is the development of a novel method of sorting cells using a droplet-sorting platform and a fluorescent calcium dye to separate cells based on CD16 recognition of cell-bound antibody. We applied this novel sorting method to visualize transcriptomic variation between NK cells that are or are not activated by binding the anti-KLRG1 antibody using RNA sequencing. The data in this study reveals a reliable and target-specific cytotoxicity of the cell depleting anti-KLRG1 antibody, and supports our droplet-sorting calcium assay as a novel method of sorting cells based on receptor activation.

Uncovering the Links Between Dietary Sugar and Cancer: A Narrative Review Exploring the Impact of Dietary Sugar and Fasting on Cancer Risk and Prevention.

Over the last several years, the scientific community has grown concerned about the relationship between dietary sugar intake and cancer development. The main causes of concern are the increasing intake of processed foods rich in sugar and the rising incidence of cancer cases. This study aims to uncover the complex relationship between sugar consumption and cancer development and its progression, with a particular focus on investigating whether fasting can protect against this condition. Our review provides a detailed discussion of the molecular aspects of the sugar-cancer relationship and an analysis of the existing literature. It explains how sugar affects cell signaling, inflammation, and hormonal pathways associated with the development of cancer. We also explored the new role of fasting in the prevention of cancer and its impact on cancer patients. This encompasses fasting-triggered autophagy, metabolic alterations, and possible health benefits, which form the major concern of this paper. Thus, by deepening the knowledge of these relations and providing the results of the analysis accompanied by concise and meaningful illustrations to facilitate the understanding of the data, we open the door to the further development of ideas to minimize the rates of cancer and improve overall well-being.

New Cytotoxic α-Aminoacylamide and bis-1,5-Disubstituted Tetrazole Adducts From Amino-Diterpene Molecules by Ugi Reaction.

In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1ß,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2-15.4 µM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.

Nanoparticle-mediated gene delivery of TRAIL to resistant cancer cells: A review.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as APO2L, has emerged as a highly potential anticancer agent because of its capacity to effectively trigger apoptosis in tumor cells by specifically binding to either of its death receptors (DR4 or DR5) while having no adverse effects on normal cells. Nevertheless, its practical use has been hindered by its inefficient pharmacokinetics characteristics, the challenges involved in its administration and delivery to targeted cells, and the resistance exhibited by most cancer cells towards TRAIL. Gene therapy, as a promising approach would be able to potentially circumvent TRAIL-based cancer therapy challenges mainly through localized TRAIL expression and generating a bystander impact. Among different strategies, using nanoparticles in TRAIL gene delivery allows for precise targeting, and overcoming TRAIL resistance by combination therapy. In this review, we go over potential mechanisms by which cancer cells achieve resistance to TRAIL and provide an overview of different carriers for delivering of the TRAIL gene to resistant cancer cells, focusing on different types of nanoparticles utilized in this context. We will also explore the challenges, and investigate future perspectives of this nanomedicine approach for cancer therapy.

Carcinomembrane-Camouflaged Perfluorochemical Dual-Layer Nanopolymersomes Bearing Indocyanine Green and Camptothecin Effectuate Targeting Photochemotherapy of Cancer.

Photochemotherapy has been recognized as a promising combinational modality for cancer treatment. However, difficulties such as off-target drug delivery, systemic toxicity, and the hypoxic nature of the tumor microenvironment remain hindrances to its application. To overcome these challenges, cancer cell membrane camouflaged perfluorooctyl bromide (PFOB) dual-layer nanopolymersomes bearing indocyanine green (ICG) and camptothecin (CPT), named MICFNS, were developed in this study, and melanoma was exploited as the model for MICFNS manufacture and therapeutic application. Our data showed that MICFNS were able to stabilize both ICG and CPT in the nanocarriers and can be quickly internalized by B16F10 cells due to melanoma membrane-mediated homology. Upon NIR irradiation, MICFNS can trigger hyperthermia and offer enhanced singlet oxygen production due to the incorporation of PFOB. With ≥10/2.5 µM ICG/CPT, MICFNS + NIR can provide comparable in vitro cancericidal effects to those caused by using an 8-fold higher dose of encapsulated CPT alone. Through the animal study, we further demonstrated that MICFNS can be quickly brought to tumors and have a longer retention time than those of free agents in vivo. Moreover, the MICFNS with 40/10 µM ICG/CPT in combination with 30 s NIR irradiation can successfully inhibit tumor growth without systemic toxicity in mice within the 14 day treatment. We speculate that such an antitumoral effect was achieved by phototherapy followed by chemotherapy, a two-stage tumoricidal process performed by MICFNS. Taken together, we anticipate that MICFNS, a photochemotherapeutic nanoplatform, has high potential for use in clinical anticancer treatment.

Development of mesoporous magnetic nanoparticles supported idarubicin and investigation of apoptotic and cytotoxic effects on cancer cell lines.

BACKGROUND: Many methods are used for cancer treatment, especially chemotherapy. In addition to the their therapeutic effects, chemotherapeutic drugs also have serious disadvantages, such as not being cell and tissue-specific, causing toxicity in many tissues, and developing drug resistance. Many methods, especially nanocarriers, have been designed to overcome these disadvantages. METHODS AND RESULTS: In this study, we synthesized mesoporous silica iron oxide nanoparticles with different pore diameters and loaded idarubicin (6MFe3O4-NH2-IDA and 35MFe3O4-NH2-IDA). The synthesized molecules were characterized using FT-IR, XRD, and SEM methods. The cytotoxic effects of unbound idarubicin and idarubicin-loaded nanoparticles on MCF7 and HL-60 cell lines were examined by MTT test. Additionally, the expression of anti-apoptotic (Survivin and BCL-2) and apoptotic (BAX, PUMA, and NOXA) genes of the nanoparticles were measured by PCR method. As a result of the analyses, it was seen that nanoparticles with the desired properties and sizes were synthesized. In MTT analysis, it was observed that both nanoparticles dramatically decreased the IC50 value in cell lines. However, the 35MFe3O4-NH2-IDA molecule was found to have lower IC50 values. IC50 values ​​for pristine IDA, 6MFe3O4-NH2, and 35MFe3O4-NH2 at 24 h were found to be 3.56, 1.24 and 0.25 µM in the MCF7 cell line and 4.15, 1.16 and 0.34 µM in the HL-60 cell line, respectively. Additionally, apoptotic gene expression increased, and anti-apoptotic gene expression decreased. CONCLUSIONS: Our study demonstrates that the effectiveness of idarubicin can be significantly enhanced by its application with mesoporous nanocarriers. This enhancement is attributed to the controlled release of idarubicin from the nanocarrier, which circumvents drug resistance mechanisms, improves drug solubility, and increases the drug-carrying capacity per unit volume due to the porous structure of the carrier. These findings underscore the potential of the synthesized nanocarrier in cancer treatment and provide a clear direction for future research in this field.

Asparagus racemosus silver chloride nanoparticles and Kaempferia rotunda mediated silver/silver chloride nanoparticles inhibit human hepatocellular and lung cancer cell lines.

Recently, we have reported that biogenic silver/silver chloride nanoparticles from Asparagus racemosus (A. racemosus-AgCl-NPs) and Kaempferia rotunda (K. rotunda-Ag/AgCl-NPs) inhibited different cancer cells by inducing apoptosis and several genes alteration. Here for the first time, we assessed the effects of these two nanoparticles on human lung (A549) and hepatocellular (SMMC-7721) carcinoma cell lines. A. racemosus-AgCl-NPs and K. rotunda-Ag/AgCl-NPs inhibited A549 cell growth with IC50 values of 22.7 and 59.7 µg/ml and the calculated IC50 values for SMMC-7721 cell were 89.3 and 126.3 µg/ml, respectively. A. racemosus-AgCl-NPs exerted higher cytotoxicity against HEK293T cells than doxorubicin and K. rotunda-Ag/AgCl-NPs. Both the nanoparticles induced apoptosis in A549 and SMMC-7721 cell lines. A significant rise of early apoptotic cells and late apoptotic cells was found for A549 cells after treatment with A. racemosus-AgCl-NPs and stained with FITC-annexin V/PI. Apoptosis in A549 cells was further confirmed by monitoring the alteration of the expression level of several genes using real-time PCR and cell cycle arrest by flowcytometry after treatment with A. racemosus-AgCl-NPs. The expression of STAT-3, TNFα, and EGFR genes was decreased with the increase of caspase-8, FAS, and FADD gene expression. G2/M cell cycle phase was arrested after treatment of A549 cells with A. racemosus-AgCl-NPs.

Immune escape between endoplasmic reticulum stress-related cancer cells and exhausted CD8+T cells leads to neoadjuvant chemotherapy resistance in ovarian cancer.

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed. While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT. Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance.

The modulation of lung cancer cell motility by Calponin 3 is achieved through its ability to sense and respond to changes in substrate stiffness.

The influence of extracellular matrix (ECM) stiffness on cell behavior is a well-established phenomenon. Tumor development is associated with the stiffening of the ECM. However, the understanding of the role of biomechanical behavior and mechanotransduction pathways in the oncogenesis of tumor cells remains limited. In this study, we constructed in vitro models using Polydimethylsiloxane substrates to create soft and stiff substrates. We then evaluated the migration of lung cancer cells A549 using video-microscopy and transwell assays. The mechanical properties were assessed through the utilization of atomic force microscopy, Optical Magnetic Twisting Cytometry, and traction force analysis. Additionally, the expression of Calponin 3 (CNN3) was evaluated using reverse transcription­quantitative PCR and immunofluorescence techniques. Our observations indicate that the presence of a stiff substrate enhances A549 motility, as evidenced by increased stiffness and traction force in A549 cells on the stiff substrate. Furthermore, we observed a decrease in CNN3 expression in A549 cells on the stiff substrate. Notably, when CNN3 was overexpressed, it effectively inhibited the migration and invasion of A549 cells on the stiff substrate. The results of our study provide novel perspectives on the mechanisms underlying cancer cell migration in response to substrate mechanical properties.

Yellow Emissive Carbon Dots - A Robust Nanoprobe for Highly Sensitive Quantification of Jaundice Biomarker and Mitochondria Targeting in Cancer Cells.

The abnormally high level of bilirubin (BR) in biofluids (human serum and urine) indicates a high probability of jaundice and liver dysfunction. However, quantification of BR as the Jaundice biomarker is difficult due to the interference of various biomolecules in serum and urine. To address this issue, we developed a fluorescence-based detection strategy, for which yellow emissive carbon dots (YCDs) were produced from a one-step solvothermal process using phloroglucinol and thionin acetate as chemical precursors. The as-fabricated YCDs exhibited a strong fluorescence peak at the wavelength of 542 nm upon excitation at 390 nm. We used YCDs for detecting BR through the fluorescence turn-off mechanism, unveiling the excellent sensitivity in the linear range of 0.5-12.5 µM with a limit of detection (LOD) of 9.62 nM, which was far below the clinically relevant range. The analytical nanoprobe also offered excellent detection specificity for quantifying BR in real samples. Moreover, the biocompatible fluorescent nanoprobe was successfully employed to target mitochondria in live cancer cells. A colocalization study confirmed that YCDs possessed the ability to target mitochondria and overlapped completely with MitoTracker Red. The developed nanoprobe of YCDs turned out to be straightforward in their synthesis, noninvasive, and can be utilized for biomedical sensors to diagnose the onset of jaundice as well as for mitochondria targeting.

Intercellular Communication Through Microtubular Highways.

Tunneling nanotubes (TNTs) are open-ended, membrane-encased extensions that connect neighboring cells. They have diameters up to 1 µm but are able to expand to convey large cargos. Lengths vary depending on the distance of the cells but have been reported to be capable of extending beyond 300 µm. They have actin cytoskeletons that are essential for their formation, and may or may not have microtubule networks. It is thought that thin TNTs lack microtubules, while thicker TNTs have microtubular highways that use motor proteins to convey materials, including proteins, mitochondria, and nanoparticles between cells. Specifically, the presence of dynein and myosin support trafficking of cargo in both directions. The purpose of these connections is to enable cells to work as a unit or to extend cell life by diluting cytotoxic agents or acquiring biological material needed to survive.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and their expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.

Nuclear receptor coactivator 7 (NCOA7) protects cancer cells from oxidative damage through its ERbd domain.

Oxidative stress causes damage to cancer cells and plays an important role in cancer therapy. Antagonizing oxidative stress is crucial for cancer cells to survive during the oxidation-based therapy. In this study, we defined the role of nuclear receptor co-activator 7 (NCOA7) in anti-oxidation in lung cancer cells and found that NCOA7 protects lung cancer A549 cells from the oxidative damage caused by hydrogen peroxide. Knockdown of NCOA7 in A549 cells significantly enhanced the hydrogen peroxide-caused inhibition of cell proliferation and migration, and markedly increased the damage effect of hydrogen peroxide on F-actin and focal adhesion structure, suggesting that NCOA7 protects F-actin and focal adhesion structure, thus the cell proliferation and migration, from oxidation-caused damage. Mechanistically, the anti-oxidation effect of NCOA7 is mediated by its nuclear receptor binding domain, the ERbd domain, suggesting that the anti-oxidation function of NCOA7 is dependent on its nuclear receptor co-activator activity. Our studies identified NCOA7 as an anti-oxidative protein through its nuclear receptor co-activator function and revealed the mechanism underlying the anti-oxidative effect of NCOA7 on cancer cell proliferation and migration.