bims-meluca 2026-08-30 papers

Med Oncol. 2026 Aug 24. pii: 254. [Epub ahead of print]43(10):

Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.

Semahat Celikten, Zafer Yildirim, Sevim Aydemir, Busra Bara, Eda Dogan, Zuhal Eroglu, Vildan Bozok.

Cisplatin-based chemotherapy remains a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC); however, the emergence of chemoresistance severely limits its clinical efficacy. Endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) have been implicated in cancer cell survival and therapy resistance, highlighting modulation of this signalling as a potential therapeutic strategy. In this study, we investigated whether pharmacological induction of endoplasmic reticulum stress via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition could attenuate cisplatin resistance in NSCLC. Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Notably, thapsigargin pre-treatment significantly reduced cisplatin IC₅₀ values and decreased resistance indices in resistant cells, indicating attenuation of the resistant phenotype. In addition, SERCA inhibition enhanced apoptotic cell death in selected models and markedly suppressed clonogenic survival and migratory capacity across all cell lines examined. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC.

Keywords: ATF4; Cisplatin resistance; Endoplasmic reticulum stress; GRP78; Non-small cell lung cancer; PERK signalling; Thapsigargin; XBP1

DOI: https://doi.org/10.1007/s12032-026-03369-5

Cancer Lett. 2026 Aug 22. pii: S0304-3835(26)00559-8. [Epub ahead of print]659 218795

Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.

Wanli Liu, Aoyi Xiao, Jingcheng Zhang, Ruizhe Zhu, Liangrui Zhou, Sumei Zhang, Zixin Zhang, Jinyuan Wang, Dingyan Cao, Huanwen Wu, Xudong Liu, Xianlin Han, Wenming Wu.

Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic 'feed-forward' axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.

Keywords: Adipose tissue remodeling; Cancer cachexia; Extracellular vesicles; Muscle wasting; Pancreatic ductal adenocarcinoma; miR-221-3p

DOI: https://doi.org/10.1016/j.canlet.2026.218795

Front Bioinform. 2026 ;6 1911554

Integrated analysis of enzymes, mRNAs, and miRNAs provides insight into the regulatory potential of extracellular vesicles in recipient cell glucose metabolism.

Namita N Kashyap, Sharath Mohan Bhat, Padmanabha Udupa E G, Kavitha S Shettigar, Vinutha R Bhat, Dinesh Upadhya.

Introduction: Extracellular vesicles (EVs) are increasingly recognized as active coordinators of metabolic processes rather than mere messengers. By carrying unique subsets of enzymes, metabolites, lipids, and nucleic acids, EVs can directly deliver functional metabolic machinery or dynamically alter intracellular metabolic fluxes in recipient cells. However, their role in regulating specific biochemical pathways remains largely unknown.
Methodology: In the current in silico analysis, we explored the dominant metabolic role of EV cargo using publicly available multi-omics data. For this, the top 500 mRNAs and proteins, along with miRNAs reported at least 10 times in humans across independent studies, as catalogued in the EVpedia database are considered and curated into a comprehensive dataset.
Results: Enrichment analysis of these mRNAs and proteins revealed that carbohydrate metabolic pathways, including glycolysis, the pentose phosphate pathway and the TCA cycle, were over-represented in EVs. Further, to investigate whether EVs carry miRNAs that regulate these pathways, we analyzed the miRNA targets. Enrichment analysis of EV miRNA targets mapped glycolytic regulatory genes, including HK1, HK2, PFKP and PKM. Interestingly, we also found miRNAs targeting genes encoding glucose transporters (SLC2A1, SLC2A3, SLC2A4, and SLC2A14) reported in EVs. Genomic annotation of these miRNAs revealed them to form clusters, including the miR-17-92 cluster, a well-known regulator of glycolysis.
Discussion: While the study has limitations-mainly due to the biological heterogeneity of EVs and the difficulty of standardizing cargo-the results potentially suggest that, by delivering enzymes, their mRNAs, regulatory miRNAs or combinations thereof, EVs could potentially mediate recipient cell glucose metabolism.

Keywords: extracellular vesicles; glucose metabolism; mRNA; miRNA; molecular regulation

DOI: https://doi.org/10.3389/fbinf.2026.1911554