Decarceration policies, enacted for SARS-CoV-2 mitigation in carceral settings, potentially exacerbated barriers to care for people living with HIV (PWH) with criminal legal involvement (CLI) during Shelter-in-Place (SIP) by limiting opportunities for engagement in provisions of HIV and behavioral health care. We compared health care engagement for PWH with CLI in San Francisco, California before and after decarceration and SIP using interrupted time series analyses. Administrative data identified PWH booked at the San Francisco County Jail with at least one clinic encounter from 01/01/2018-03/31/2020 within the municipal health care network.
View Article and Find Full Text PDFInhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways.
View Article and Find Full Text PDFThe small molecule erastin inhibits the cystine-glutamate antiporter, system x, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied.
View Article and Find Full Text PDFMechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet.
View Article and Find Full Text PDFAltered metabolism is a common feature of new and recurring malignancy. In this issue of Cancer Cell, Reina-Campos and colleagues report upregulation of the serine, glycine, one-carbon (SGOC) metabolic network is required for neuroendocrine prostate cancer, a castration-resistant aggressive form of the disease, and presents a targetable vulnerability.
View Article and Find Full Text PDFPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue.
View Article and Find Full Text PDFThe tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation.
View Article and Find Full Text PDFPhosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism.
View Article and Find Full Text PDFOne of the hallmarks of cancer is the ability to reprogram cellular metabolism to increase the uptake of necessary nutrients such as glucose and glutamine. Driven by oncogenes, cancer cells have increased glutamine uptake to support their highly proliferative nature. However, as cancer cells continue to replicate and grow, they lose access to vascular tissues and deplete local supply of nutrients and oxygen.
View Article and Find Full Text PDFAcetate is a major nutrient that supports acetyl-coenzyme A (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. However, its source is unclear. Here, we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals.
View Article and Find Full Text PDFCell proliferation can be dependent on the non-essential amino acid serine, and dietary restriction of serine inhibits tumor growth, but the underlying mechanisms remain incompletely understood. Using a metabolomics approach, we found that serine deprivation most predominantly impacts cellular acylcarnitine levels, a signature of altered mitochondrial function. Fuel utilization from fatty acid, glucose, and glutamine is affected by serine deprivation, as are mitochondrial morphological dynamics leading to increased fragmentation.
View Article and Find Full Text PDFDriven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage.
View Article and Find Full Text PDFNearly 3% of the human population carries bi-allelic loss-of-function variants in the gene encoding CLYBL. While largely healthy, these individuals exhibit reduced circulating vitamin B levels. In this issue of Cell, Shen and colleagues uncover the metabolic role of CLYBL, linking its function to B metabolism and the immunomodulatory metabolite, itaconate.
View Article and Find Full Text PDFNat Cell Biol
November 2017
The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.
View Article and Find Full Text PDFCancer cells have epigenetic alterations that are known to drive cancer progression. The reversibility of the epigenetic posttranslational modifications on chromatin and DNA renders targeting these modifications an attractive means for cancer therapy. Cellular epigenetic status interacts with cell metabolism, and we are now beginning to understand the nature of how this interaction occurs and the biological contexts that mediate its function.
View Article and Find Full Text PDFPoorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids.
View Article and Find Full Text PDFGlutamine is an essential nutrient for cancer cell survival and proliferation. Enhanced utilization of glutamine often depletes its local supply, yet how cancer cells adapt to low glutamine conditions is largely unknown. Here, we report that IκB kinase β (IKKβ) is activated upon glutamine deprivation and is required for cell survival independently of NF-κB transcription.
View Article and Find Full Text PDFChanges in cellular oxygen tension play important roles in physiological processes including development and pathological processes such as tumor promotion. The cellular adaptations to sustained hypoxia are mediated by hypoxia-inducible factors (HIFs) to regulate downstream target gene expression. With hypoxia, the stabilized HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-β) heterodimer bind to hypoxia response elements (HREs) and regulate expression of target genes.
View Article and Find Full Text PDFDespite advances in our understanding of protein kinase regulation in the DNA damage response, the mechanism that controls protein phosphatase activity in this pathway is unclear. Unlike kinases, the activity and specificity of serine/threonine phosphatases is governed largely by their associated proteins. Here we show that Tip41-like protein (TIPRL), an evolutionarily conserved binding protein for PP2A-family phosphatases, is a negative regulator of protein phosphatase 4 (PP4).
View Article and Find Full Text PDFBackground: (V600) BRAF mutations drive approximately 50% of metastatic melanoma which can be therapeutically targeted by BRAF inhibitors (BRAFi) and, based on resistance mechanisms, the combination of BRAF and MEK inhibitors (BRAFi + MEKi). Although the combination therapy has been shown to provide superior clinical benefits, acquired resistance is still prevalent and limits the overall survival benefits. Recent work has shown that oncogenic changes can lead to alterations in tumor cell metabolism rendering cells addicted to nutrients, such as the amino acid glutamine.
View Article and Find Full Text PDFUnlabelled: Jumonji domain-containing protein 3 (JMJD3/KDM6B) demethylates lysine 27 on histone H3 (H3K27me3), a repressive epigenetic mark controlling chromatin organization and cellular senescence. To better understand the functional consequences of JMJD3 its expression was investigated in brain tumor cells. Querying patient expression profile databases confirmed JMJD3 overexpression in high-grade glioma.
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