SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition.

Direct targeting of the -mutant protein using covalent inhibitors (G12Ci) acts on human non-small cell lung cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma.

Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer.

Lipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells.

Fluorogenic Probes for Intracellular Iron Detection.

Iron is a crucial element required to sustain multiple biological processes, including oxygen transport, DNA synthesis, and electron transport. In living cells, iron exists as either ferrous iron (Fe) or ferric iron (Fe), and its redox forms are regulated by the labile iron pool. Both iron deficiency and excess can lead to a range of pathological conditions, such as anemia, cancer, neurodegenerative disorders, and ischemia and reperfusion injury.

The Dual Role of ACOD1 in Inflammation.

Immunometabolism is an interdisciplinary field that focuses on the relationship between metabolic pathways and immune responses. Dysregulated immunometabolism contributes to many pathological settings, such as cytokine storm or immune tolerance. Aconitate decarboxylase 1 (ACOD1, also known as immunoresponsive gene 1), the mitochondrial enzyme responsible for catalyzing itaconate production, was originally identified as a bacterial LPS-inducible gene involved in innate immunity in mouse macrophages.

Mitochondrial ACOD1/IRG1 in infection and sterile inflammation.

Immunometabolism is a dynamic process involving the interplay of metabolism and immune response in health and diseases. Increasing evidence suggests that impaired immunometabolism contributes to infectious and inflammatory diseases. In particular, the mitochondrial enzyme aconitate decarboxylase 1 (ACOD1, best known as immunoresponsive gene 1 [IRG1]) is upregulated under various inflammatory conditions and serves as a pivotal regulator of immunometabolism involved in itaconate production, macrophage polarization, inflammasome activation, and oxidative stress.

Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis.

Sepsis is a challenging clinical syndrome caused by a dysregulated host response to infection. Here, we identified an unexpected proseptic activity of aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages. Previous studies have suggested that ACOD1, also known as immune-responsive gene 1, is an immunometabolic regulator that favors itaconate production to inhibit bacterial lipopolysaccharide-induced innate immunity.

COL5A1 Promotes the Progression of Gastric Cancer by Acting as a ceRNA of miR-137-3p to Upregulate FSTL1 Expression.

MicroRNAs (miRNAs) and their target genes have been shown to play an important role in gastric cancer but have not been fully clarified. Therefore, our goal was to identify the key miRNA-mRNA regulatory network in gastric cancer by utilizing a variety of bioinformatics analyses and experiments. A total of 242 miRNAs and 1080 genes were screened from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively.

The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity.

ACOD1 (also known as IRG1) has emerged as a regulator of immunometabolism that operates by producing metabolite itaconate. Here, we report a key role of STING1 (also known as STING and TMEM173) in mediating ACOD1 expression in myeloid cells in response to toll-like receptor (TLR) signaling. The activation of STING1 through exogenous cyclic dinucleotides (e.

Upstream open reading frames mediate autophagy-related protein translation.

Macroautophagy/autophagy, a highly conserved catabolic pathway that maintains proper cellular homeostasis is stringently regulated by numerous autophagy-related (Atg) proteins. Many studies have investigated autophagy regulation at the transcriptional level; however, relatively little is known about translational control. Here, we report the upstream open reading frame (uORF)-mediated translational control of multiple Atg proteins in and in human cells.

Identification and Validation of Ferroptosis-Related LncRNA Signatures as a Novel Prognostic Model for Colon Cancer.

Background: Ferroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function.

PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability.

The RNA binding protein PTBP3 was recently reported to play a critical role in multiple cancers, and the molecular mechanisms involved RNA splicing, 3' end processing and translation. However, the role of PTBP3 in colorectal cancer (CRC) remains poorly explored. Herein, PTBP3 was upregulated in CRC and associated with a poor prognosis.

Inflammasome-Dependent Coagulation Activation in Sepsis.

Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells.

Pharmacological Modulation of BET Family in Sepsis.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production.

The BET family in immunity and disease.

Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.

Tumor heterogeneity in autophagy-dependent ferroptosis.

Macroautophagy (hereafter referred to as "autophagy") is a lysosome-mediated degradation process that plays a complex role in cellular stress, either promoting survival or triggering death. Early studies suggest that ferroptosis, an iron-dependent form of regulated cell death, is not related to autophagy. Conversely, recent evidence indicates that the molecular machinery of autophagy facilitates ferroptosis through the selective degradation of anti-ferroptosis regulators.

The long noncoding RNA LUCAT1 promotes colorectal cancer cell proliferation by antagonizing Nucleolin to regulate MYC expression.

The long noncoding RNA (lncRNA) LUCAT1 was recently reported to be upregulated and to play an essential role in multiple cancer types, especially colorectal cancer (CRC), but the molecular mechanisms of LUCAT1 in CRC are mostly unreported. Here, a systematic analysis of LUACT1 expression is performed with data from TCGA database and clinic CRC samples. LUCAT1 is identified as a putative oncogene, which is significantly upregulated in CRC and is associated with poor prognosis.

CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer.

Objective: Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).

Design: We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line.

High expression of miR-135b predicts malignant transformation and poor prognosis of gastric cancer.

Aims: MiR-135b is a downstream effector of oncogenic signaling pathways. This study aimed to reveal the underlying regulation and significance of miR-135b in gastric cancer.

Materials And Methods: The influence of Wnt and PI3K/AKT signaling pathways on the transcriptional activation of the miR-135b promoter was determined by dual-luciferase reporter assays.

ACOD1 in immunometabolism and disease.

Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals. Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is emerging as a regulator of immunometabolism in inflammation and infection. Upregulation of ACOD1 expression occurs in activated immune cells (e.

ERBB4 promotes the progression of inflammatory breast cancer through regulating PDGFRA.

Background: The regulatory roles of human epidermal growth factor receptor [erb-b2 receptor tyrosine kinase 4 (ERBB)] family in tumors was received widespread attention. Although ERBB4 was crucial regulator in metastasis of malignant tumors, the exact mechanism of ERBB4 in inflammatory breast cancer (IBC) remains unclarified.

Methods: In this study, we collected IBC tissues and cell lines, and explored the expression levels of ERBB4 and platelet-derived growth factor receptor alpha (PDGFRA) using real-time quantitative polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and western blot assays.

TMEM173 Drives Lethal Coagulation in Sepsis.

The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes.

PLAGL2 and POFUT1 are regulated by an evolutionarily conserved bidirectional promoter and are collaboratively involved in colorectal cancer by maintaining stemness.

Background: Our previous study revealed that PLAGL2 or POFUT1 can promote tumorigenesis and maintain significant positive correlations in colorectal cancer (CRC). However, the mechanism leading to the co-expression and the underlying functional and biological implications remain unclear.

Methods: Clinical tumor tissues and TCGA dataset were utilized to analyze the co-expression of PLAGL2 and POFUT1.

YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma.

YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1) is a core factor in RNA methylation modification. Recent studies have shown that m6A is closely related to multiple tumors, thus YTHDF1 may also play a role in tumorigenesis. This study, aimed to explore the role of YTHDF1 in the colorectal cancer (CRC).

DEAD-box helicase 27 plays a tumor-promoter role by regulating the stem cell-like activity of human colorectal cancer cells.

Background: Cancer stem cells (CSCs) are responsible for all important characteristics of tumors. DEAD-box helicase 27 (DDX27) is a member of the DEAD-box RNA helicase family, and there have been only a few studies on DDX27 function in cancer cells. This study is aimed at exploring whether DDX27 has any relation to tumorigenesis of colorectal cancer (CRC) and elucidating the potential mechanism.

POFUT1 promotes colorectal cancer development through the activation of Notch1 signaling.

Copy number variations (CNVs) are key drivers of colorectal cancer (CRC). Our previous studies revealed that protein O-fucosyltransferase 1 (POFUT1) overexpression is driven by CNVs during CRC development. The potential role and underlying mechanisms of POFUT1 in CRC were not investigated.