Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

Background: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor.

The integrated stress response in cancer progression: a force for plasticity and resistance.

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression.

PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy.

The efficacy of immunotherapy is limited by the paucity of T cells delivered and infiltrated into the tumors through aberrant tumor vasculature. Here, we report that phosphoglycerate dehydrogenase (PHGDH)-mediated endothelial cell (EC) metabolism fuels the formation of a hypoxic and immune-hostile vascular microenvironment, driving glioblastoma (GBM) resistance to chimeric antigen receptor (CAR)-T cell immunotherapy. Our metabolome and transcriptome analyses of human and mouse GBM tumors identify that PHGDH expression and serine metabolism are preferentially altered in tumor ECs.

Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function.

The cap-binding protein eukaryotic initiation factor 4E (eIF4E) promotes translation of mRNAs associated with proliferation and survival and is an attractive target for cancer therapeutics. Here, we used germline and conditional knockout models to assess the impact of reduced gene dosage on B-cell leukemogenesis compared to effects on normal pre-B and mature B-cell function. Using a BCR-ABL-driven pre-B-cell leukemia model, we find that loss of one allele of impairs transformation and reduces fitness in competition assays and .

The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity.

Obesity is a global epidemic leading to increased mortality and susceptibility to comorbidities, with few viable therapeutic interventions. A hallmark of disease progression is the ectopic deposition of lipids in the form of lipid droplets in vital organs such as the liver. However, the mechanisms underlying the dynamic storage and processing of lipids in peripheral organs remain an outstanding question.

Author Correction: ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation.

Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance.

The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. A substantial fraction of the immunopeptidome derives from rapidly degraded nascent polypeptides (DRiPs). By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression.

Development of a stress response therapy targeting aggressive prostate cancer.

Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown.

Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase.

KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis.

Noninvasive Measurement of mTORC1 Signaling with Zr-Transferrin.

mTOR regulates many normal physiological processes and when hyperactive can drive numerous cancers and human diseases. However, it is very challenging to detect and quantify mTOR signaling noninvasively in clinically relevant animal models of disease or man. We hypothesized that a nuclear imaging tool measuring intracellular mTOR activity could address this unmet need.

Differential Requirements for eIF4E Dose in Normal Development and Cancer.

eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation.

Translational control of the cytosolic stress response by mitochondrial ribosomal protein L18.

In response to stress, cells attenuate global protein synthesis but permit efficient translation of mRNAs encoding heat-shock proteins (HSPs). Although decades have passed since the first description of the heat-shock response, how cells achieve translational control of HSP synthesis remains enigmatic. Here we report an unexpected role for mitochondrial ribosomal protein L18 (MRPL18) in the mammalian cytosolic stress response.

Nutrient signaling in protein homeostasis: an increase in quantity at the expense of quality.

The discovery that rapamycin extends the life span of diverse organisms has triggered many studies aimed at identifying the underlying molecular mechanisms. Mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and may regulate organismal aging by controlling mRNA translation. However, how inhibiting mTORC1 and decreasing protein synthesis can extend life span remains an unresolved issue.

mTOR signaling in protein homeostasis: less is more?

A proper balance between synthesis, maturation and degradation of cellular proteins is crucial for cells to maintain physiological functions. The costly process of protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin (mTOR), whereas the quality of newly synthesized polypeptides is largely maintained by molecular chaperones and the ubiquitin-proteasome system. There is a wealth of evidence indicating close ties between the nutrient signaling pathway and the intracellular stress response.

PI3K-mTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation.

Protein synthesis is a key regulated cellular process that links nutrient availability and organismal growth. It has long been known that some cellular proteins continue to be synthesized under conditions where global translation is severely compromised. One prominent example is the selective translation of heat shock proteins (Hsps) under stress conditions.