Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.

Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling.

Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling.

The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood.

A Novel Role for RNF126 in the Promotion of G2 Arrest via Interaction With 14-3-3σ.

Purpose: Cell cycle checkpoints and DNA repair are important for cell survival after exogenous DNA damage. Both rapid blockage of G2 to M phase transition in the cell cycle and the maintenance of relatively slow G2 arrest are critical to protect cells from lethal ionizing radiation (IR). Checkpoint kinase 1 is pivotal in blocking the transition from G2 to M phases in response to IR.

ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction.

The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation.

A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors.

There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non-small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition.

The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation.

N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its 'reader' YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1.

Protein phosphatase 2A controls ongoing DNA replication by binding to and regulating cell division cycle 45 (CDC45).

Genomic replication is a highly regulated process and represents both a potential benefit and liability to rapidly dividing cells; however, the precise post-translational mechanisms regulating genomic replication are incompletely understood. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that regulates a diverse array of cellular processes. Here, utilizing both a gain-of-function chemical biology approach and loss-of-function genetic approaches to modulate PP2A activity, we found that PP2A regulates DNA replication.

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy.

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms.

Lipid metabolism reprogramming and its potential targets in cancer.

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources.

Lipid droplets, potential biomarker and metabolic target in glioblastoma.

Lipid droplets (LDs) are subcellular organelles that store large amounts of the neutral lipids, triglycerides (TG) and/or cholesteryl esters (CE). LDs are commonly formed in adipocytes, liver cells and macrophages, and their formation has been shown to be associated with the progression of metabolic diseases, i.e.

microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism.

The membrane-bound transcription factors, SREBPs (sterol regulatory element-binding proteins), play a central role in regulating lipid metabolism. The transcriptional activation of SREBPs requires the key protein SCAP (SREBP-cleavage activating protein) to translocate their precursors from the endoplasmic reticulum to the Golgi for subsequent proteolytic activation, a process tightly regulated by a cholesterol-mediated negative feedback loop. Our previous work showed that the SCAP/SREBP-1 pathway is significantly upregulated in human glioblastoma (GBM), the most deadly brain cancer, and that glucose-mediated -glycosylation of SCAP is a prerequisite step for SCAP/SREBP trafficking.