Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia.

The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here, we show an additional feature of the developing nervous system that causes neural debris-promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood.

Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer.

Ferroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides.

Ketogenic Diet Alters the Epigenetic and Immune Landscape of Prostate Cancer to Overcome Resistance to Immune Checkpoint Blockade Therapy.

Unlabelled: Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models.

Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides.

Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1).

Sensitization of cancer cells to ferroptosis coincident with cell cycle arrest.

Ferroptosis is a non-apoptotic form of cell death that can be triggered by inhibiting the system x cystine/glutamate antiporter or the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). We have investigated how cell cycle arrest caused by stabilization of p53 or inhibition of cyclin-dependent kinase 4/6 (CDK4/6) impacts ferroptosis sensitivity. Here, we show that cell cycle arrest can enhance sensitivity to ferroptosis induced by covalent GPX4 inhibitors (GPX4i) but not system x inhibitors.

Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides.

Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1).

Regulators mount up: the metabolic roles of apoptotic proteins.

The induction of apoptosis, a programmed cell death pathway governed by activation of caspases, can result in fundamental changes in metabolism that either facilitate or restrict the execution of cell death. In addition, metabolic adaptations can significantly impact whether cells in fact initiate the apoptotic cascade. In this mini-review, we will highlight and discuss the interconnectedness of apoptotic regulation and metabolic alterations, two biological outcomes whose regulators are intertwined.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation.

Assessment of Metabolic Pathways and Parameters in Extracellular Matrix-Detached Cells.

Changes in metabolism can alter a variety of distinct cellular parameters in a number of physiological and pathological contexts. Relatedly, the loss of integrin-mediated attachment to extracellular matrix (ECM) is now appreciated to alter metabolism in a variety of distinct fashions. As such, assays to quantify and assess metabolism during ECM detachment are critical to better understanding the cellular and molecular changes that impact the behavior and survival of ECM-detached cells.

Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells.

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis.

Microglia cannibalism and efferocytosis leads to shorter lifespans of developmental microglia.

The overproduction of cells and subsequent production of debris is a universal principle of neurodevelopment. Here we show an additional feature of the developing nervous system that causes neural debris - promoted by the sacrificial nature of embryonic microglia that irreversibly become phagocytic after clearing other neural debris. Described as long-lived, microglia colonize the embryonic brain and persist into adulthood.

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells.

In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation.

SGK1-regulated metabolism: key for the survival of cells detached from the extracellular matrix.

Cells that lack attachment to the extracellular matrix (ECM) experience metabolic defects that can lead to caspase-independent cell death. Recently, we discovered that serum and glucocorticoid kinase-1 (SGK1) plays a critical role in the regulation of glucose metabolism, the promotion of energy production, and ultimately the survival of ECM-detached cells. : ECM, extracellular matrix; SGK1, serum and glucocorticoid kinase-1; ROS, reactive oxygen species; CCCP, cyanide m-chlorophenyl hydrazine; PPP, pentose phosphate pathway; G3P, glyceraldhyde-3-phosphate; shRNA, short hairpin RNA; TCA, tricarboxylic acid.

Occupational Reflection as Intervention in Inpatient Psychiatry.

Importance: The recovery model in mental health involves person-driven care and informed decision making to enhance engagement in meaningful activities and inclusion in society. To facilitate the recovery process, occupational therapy practitioners must support their clients in understanding how their participation in meaningful occupation is intimately related to their health and well-being.

Objective: To explore whether engaging in an occupational reflection intervention on an inpatient psychiatric unit can support the recovery of adults living with serious mental illness (SMI).

Oncogenic signaling inhibits c-FLIP expression and its non-apoptotic function during ECM-detachment.

Inhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance.

SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells.

Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death.

UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.

Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized.

Mitochondrial Reactive Oxygen Species and Mitophagy: A Complex and Nuanced Relationship.

Mitochondria represent a major source of intracellular reactive oxygen species (ROS) generation. This is often a consequence of oxidative phosphorylation, which can produce ROS as a result of leakage from the electron transport chain. In addition, quality control mechanisms exist to protect cells from cytotoxic ROS production.

Antioxidant Defenses: A Context-Specific Vulnerability of Cancer Cells.

Reactive oxygen species (ROS) are well known for their capacity to cause DNA damage, augment mutagenesis, and thereby promote oncogenic transformation. Similarly, agents that reduce ROS levels (antioxidants) are frequently thought to have anti-cancer properties given their propensity to minimize DNA damage and mutagenesis. However, numerous clinical studies focused on antioxidants suggest that this is a facile premise and that antioxidant capacity can be important for cancer cells in a similar fashion to normal cells.

RIPK1-dependent mitophagy: A novel mechanism to eliminate cells detached from the extracellular matrix.

For cancer cells to survive during extracellular matrix (ECM)-detachment, they must inhibit anoikis and rectify metabolic deficiencies that lead to the induction of non-apoptotic cell death. Here, we highlight and discuss our recent study implicating receptor-interacting protein kinase-1 (RIPK1) in the induction of mitophagy, the production of reactive oxygen species (ROS) and the consequent elimination of ECM-detached cells.

RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells.

For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment.

Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment.

Nontransformed cells that become detached from the extracellular matrix (ECM) undergo dysregulation of redox homeostasis and cell death. In contrast, cancer cells often acquire the ability to mitigate programmed cell death pathways and recalibrate the redox balance to survive after ECM detachment, facilitating metastatic dissemination. Accordingly, recent studies of the mechanisms by which cancer cells overcome ECM detachment-induced metabolic alterations have focused on mechanisms in redox homeostasis.

Collapsing the Metabolic PON2zi Scheme in Pancreatic Ductal Adenocarcinoma.

A hallmark of pancreatic ductal adenocarcinoma cancer (PDAC) cells is metabolic reprogramming that facilitates tumor progression. In a recent paper published in Molecular Cell, Nagarajan et al. discover that paraoxonase (PON)2 stimulates glucose transporter (GLUT)1-mediated glucose uptake, prevents AMP-activated protein kinase (AMPK)-mediated anoikis, and consequently promotes PDAC development and metastasis.