bims-stacyt 2026-02-01 papers

Cells. 2026 Jan 20. pii: 188. [Epub ahead of print]15(2):

Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.

Cells are continuously exposed to physiological and environmental stressors that disrupt homeostasis, triggering adaptive mechanisms such as the integrated stress response (ISR). A central feature of ISR is the selective translation of activating transcription factor 4 (ATF4), which orchestrates gene programs essential for metabolic adaptation and survival. Stress-induced acute ATF4 expression occurs in diverse mammalian cell types and is typically protective; however, chronic activation contributes to pathologies including cancer and neurodegeneration. Canonical ISR (c-ISR) is initiated by phosphorylation of eIF2α in response to stressors such as endoplasmic reticulum or mitochondrial dysfunction, hypoxia, nutrient deprivation, and infections. This modification suppresses global protein synthesis while promoting ATF4 translation through upstream open reading frames (uORFs) in its 5'UTR. Recently, an alternative pathway, split ISR (s-ISR), enabling ATF4 translation independently of eIF2α phosphorylation, was identified in mice, suggesting ISR adaptability, though its relevance in humans remains unclear. Under normal conditions, cap-dependent translation predominates, mediated by the eIF4F complex and requiring the activity of eIF2B at its initial steps. During translational stress, eIF2α phosphorylation inhibits eIF2B activity, resulting in the formation of stalled initiation complexes, which can aggregate into stress granules (SGs). SGs sequester mRNAs and translation initiation factors, further repressing global translation, while ATF4 mRNA largely escapes sequestration, enabling selective translation. This partitioning highlights a finely tuned regulatory mechanism balancing ATF4 expression during stress. Recent advances reveal that, beyond cis-regulatory uORFs, trans-acting factors such as translation initiation factors and associated RNA-binding proteins critically influence ATF4 translation. Understanding these mechanisms provides insight into ISR plasticity and its implications for development, aging, and disease.

Keywords: ATF4 mRNA; RNA demethylases; RNA-binding proteins; eIFs; integrated stress response; stress granules; translation regulation; uORFs

DOI: https://doi.org/10.3390/cells15020188

Mol Ther. 2026 Jan 28. pii: S1525-0016(26)00033-X. [Epub ahead of print]

Tumor Cell AMPK Activation Enhances NK Cell Anti-tumor Immunity and Synergizes with PD-L1 Blockade Therapy.

Zhen Lu, Jiacheng Bi, Chaoyue Zheng, Lulu Cui, Houjun Xia, Xiaochun Wan, Youhai H Chen.

Immune checkpoint blockade targeting the PD-1 or PD-L1 pathway has shown great clinical results, but only in a small subpopulation of cancer patients. The underlying mechanism of resistance to immune checkpoint therapy remains largely elusive. AMP-activated protein kinase (AMPK) senses metabolic stress, restores energy balance, and plays important roles in tumorigenesis. Here we report that tumor cell-intrinsic AMPK activation dictates the sensitivity of tumor cells to PD-L1 immunotherapy and NK cell-mediated antitumor immunity. PD-L1 checkpoint blockade resulted in increased phosphorylation of AMPK in anti-PD-L1 responsive, but not nonresponsive tumors. Pharmacological inhibition of AMPK activation diminished the therapeutic effect of PD-L1 checkpoint blockade. Conversely, pharmacological or genetic activation of AMPK in cancer cells sensitized them to NK cell-mediated killing through perforin, and synergized with PD-L1 blockade therapy to suppress tumor growth in mice in an NK cell-dependent manner. Transcriptomic analyses revealed that AMPK activation in tumor cells triggered the expression of pattern recognition receptor genes and a chemokine gene expression signature that is associated with longer overall survival of cancer patients. These findings indicate that AMPK controls tumor responsiveness to checkpoint blockade therapy through NK cell-dependent mechanisms.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.032

J Cell Sci. 2026 Jan 27. pii: jcs.264040. [Epub ahead of print]

Glucose deprivation induces AMPK-dependent α-actinin-4 expression to sustain energy efficient non-proteolytic migration.

Vividha Raunekar, Sumon Kumar Saha, Nikita Sharma, Sarbajeet Dutta, Madhurima Sarkar, Harsha Rani, Neha Deshpande, Shraddha Sansidha Mohanty, Anchita Gopikrishnan, Krithjgnan Bhardhwaj, Sudiksha Mishra, Annapoorni Rangarajan, Ramray Bhat, Vijayalakshmi Mahadevan, Shamik Sen.

Crosstalk between tumor microenvironmental factors, such as, extracellular matrix (ECM) stiffness and metabolic pathways, regulate cell invasive phenotype in cancer cells. ECM stiffening leads to the collapse of blood vessels leading to oxygen deprivation and nutrient stress. The individual and combined effect of these two factors on the mode of invasion of cancer cells remains poorly understood. Here we show that in breast cancer cells, glucose deprivation induces a switch from an energy demanding proteolytic mode of migration to an energy efficient non-proteolytic mode of migration. Energy demands met by OXPHOS, and nuclear softening sustain this mode of migration. We further show that the energy sensor AMPK mediates this switch through transcriptional activation of the mechanoresponsive actin crosslinking protein α-actinin-4. Collectively, our results demonstrate how AMPK fine-tunes mode of invasion under nutrient constraints by transcriptional activation of α-actinin-4.

Keywords: ACTN4; AMPK; Energy requirements; Invasion

DOI: https://doi.org/10.1242/jcs.264040

Cancers (Basel). 2026 Jan 18. pii: 294. [Epub ahead of print]18(2):

Metabolic Crosstalk in Triple-Negative Breast Cancer Lung Metastasis: Differential Effects of Vitamin D and E in a Co-Culture System.

Balquees Kanwal, Saranya Pounraj, Rumeza Hanif, Zaklina Kovacevic.

Background: Triple-negative breast cancer (TNBC) is more likely to metastasise to the lungs than other breast cancer (BrCa) types, yet the molecular interactions within the tumour microenvironment (TME) at secondary sites remain poorly understood. Methods: This pilot study aimed to explore the metabolic crosstalk between MDA-MB-231 TNBC cells and MRC-5 lung fibroblasts within a co-culture system to replicate the lung metastatic TME. Co-cultures were also treated with Vitamin D or Vitamin E to evaluate the effects of these nutraceuticals on the metabolic crosstalk between TNBC cells and fibroblasts. Results: Our findings demonstrate that co-culture induced the activation of fibroblasts into cancer-associated fibroblasts (CAFs), evidenced by increased α-SMA and FAP expression. Metabolic profiling revealed that TNBC cells in co-culture displayed increased expression of enzymes associated with oxidative phosphorylation (OXPHOS) and glutamine metabolism, while fibroblasts exhibited a metabolic profile consistent with glycolysis and lactate metabolism. Vitamin D inhibited lactate metabolism and HIF-1α expression in fibroblasts while suppressing TCA cycle activity in cancer cells, suggesting a potential role in disrupting oncogenic metabolic crosstalk. Conversely, Vitamin E treatment was associated with increased expression of TCA cycle and oxidative metabolism-related markers in BrCa cells without significantly affecting fibroblast glycolysis. Such differential metabolic responses may contribute to metabolic heterogeneity within the tumour microenvironment. Conclusions: These results provide valuable insights into the metabolic dynamics of TNBC metastases in the lung TME and demonstrate that Vitamins D and E exert distinct effects on metabolic crosstalk between cancer cells and fibroblasts. These findings may have significant implications for the potential supplementation of Vitamins D and E in patients with metastatic TNBC and justify further in-depth analysis.

Keywords: breast cancer; co-culture model; lung fibroblasts; triple-negative breast cancer (TNBC); tumour microenvironment; vitamin D; vitamin E

DOI: https://doi.org/10.3390/cancers18020294