bims-meluca 2026-01-04 papers

ACS Nano. 2025 Dec 31.

Copper-Oxamate Coordination Polymers Reverse Cuproptosis Resistance in Nonsmall Cell Lung Cancer via Glycolysis Reprogramming.

Hui Liu, Jianzhi Mao, Mengxin Wang, Qiwei Tian, Qianqian Cai, Lu An.

Cuproptosis, a recently identified regulated cell death pathway, is emerging as a promising therapeutic target for cancer. However, nonsmall cell lung cancer (NSCLC) exhibits inherent resistance to copper-induced toxicity, which is primarily due to enhanced glycolytic activity. Herein, a coordination polymer (Cu-Ox@HA) is designed by the chelation of copper ions with the glycolysis inhibitor oxamate (Ox), using hyaluronic acid (HA) as a biocompatible template. In the tumor microenvironment, Cu-Ox@HA disassembles in response to glutathione (GSH), enabling the synchronous release of copper ions and Ox. GSH depletion facilitates the reduction of Cu(II) to Cu(I), which exhibits high binding affinity to lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and thereby triggers DLAT oligomerization and subsequent cuproptosis. Meanwhile, the released Ox suppresses lactate dehydrogenase A, which blocks the pyruvate-to-lactate conversion in the glycolytic pathway and disrupts tumor cell energy metabolism. Thus, this nanoplatform promotes the cuproptosis response of NSCLC by glycolytic reprogramming. Both in vitro and in vivo results demonstrate that metabolic reprogramming converts tumor cells' metabolism from glycolysis to oxidative phosphorylation and overcomes intrinsic cuproptosis resistance. Moreover, in vivo studies using A549 xenograft models confirm tumor growth inhibition and prolonged survival of treated mice, verifying the therapeutic potential of this strategy. Overall, this work presents a nanomedicine approach for reversing cuproptosis resistance through metabolic-copper synergy, providing mechanistic insights for NSCLC treatment.

Keywords: copper-oxamate complex; cuproptosis; glycolysis; metabolic reprogramming; nonsmall cell lung cancer

DOI: https://doi.org/10.1021/acsnano.5c15968

Biomedicines. 2025 Dec 15. pii: 3087. [Epub ahead of print]13(12):

Asparagine synthetase (ASNS) Drives Tumorigenicity in Small Cell Lung Cancer.

Minho Jeong, Beom Chang Kim, Hyoung Jin Choi, Gyu Tae Lee, Sang-Min Jang, Kee-Beom Kim.

Objectives: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by rapid proliferation, early metastasis, and limited therapeutic response. Metabolic reprogramming is increasingly recognized as a key feature of small cell lung cancer progression, yet the contribution of specific metabolic enzymes remains incompletely understood. This study aimed to investigate the role of asparagine synthetase in small cell lung cancer tumorigenicity and disease progression. Methods: Integrative analyses were performed using public transcriptomic datasets, proteomic profiling, and functional assays in vitro and in vivo. Asparagine synthetase expression levels were evaluated in normal lung, non-small cell lung cancer, and small cell lung cancer tissues using public microarray datasets. Loss of function studies were conducted using shRNA mediated knockdown in murine and human small cell lung cancer cell models. Tumor growth and survival were assessed using xenograft mouse models. Results: Asparagine synthetase expression was significantly elevated in small cell lung cancer compared with normal lung and non-small cell lung cancer tissues. Genetic depletion of asparagine synthetase impaired cellular proliferation and colony forming capacity in vitro. In vivo, asparagine synthetase knockdown suppressed tumor growth and was associated with prolonged survival in xenograft mouse models. Conclusions: These findings demonstrate that asparagine synthetase contributes to tumor growth and metabolic adaptability in small cell lung cancer. The results support a functional role for asparagine synthetase in malignant progression and suggest that targeting asparagine metabolism may represent a potential therapeutic approach in aggressive small cell lung cancer.

Keywords: ASNS; SCLC; oncogene; progression; ribosome biogenesis

DOI: https://doi.org/10.3390/biomedicines13123087

Front Cell Dev Biol. 2025 ;13 1693023

Endoplasmic reticulum stress in non-small cell lung cancer: a review of therapeutic agents, mechanistic insights, and implications for therapy.

Qiong Luo, Xinxin Gao, Peng Meng, Xiao Qi, Wen Wang, Shan Li, Linlin Duan.

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapy resistance significantly hindering treatment efficacy. This review explores the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in NSCLC progression and resistance mechanisms. Under stress conditions such as hypoxia, nutrient deprivation, or therapeutic insult, the UPR balances adaptive survival signaling and apoptotic pathways. Key UPR sensors-PERK, IRE1α, and ATF6-are dysregulated in NSCLC, enabling tumor cells to evade death despite microenvironmental or treatment-induced stress. Preclinical studies highlight therapeutic strategies targeting ER stress through reactive oxygen species (ROS) induction, calcium homeostasis disruption, and proteasome inhibition, which shift the UPR toward pro-apoptotic outcomes. Agents such as proteasome inhibitors, natural compounds, and repurposed drugs demonstrate the potential to overcome resistance by enhancing chemosensitivity, reversing chemoresistance, and improving radiosensitivity. Combination therapies synergize ER stress inducers with conventional treatments, leveraging immunogenic cell death (ICD) to augment anti-tumor immunity. However, challenges persist due to the UPR's context-dependent outputs and the gap between preclinical models and clinical applicability. Future directions include optimizing combination regimens, identifying predictive biomarkers, and advancing personalized approaches. Translating these insights into clinical trials is critical to validate ER stress modulation as a viable strategy for improving NSCLC outcomes, offering a promising avenue to address unmet needs in this aggressive malignancy.

Keywords: endoplasmic reticulum stress; immunogenic cell death; non-small cell lung cancer; therapy resistance; unfolded protein response

DOI: https://doi.org/10.3389/fcell.2025.1693023

In Vivo. 2026 Jan-Feb;40(1):40(1): 108-122

Increased Expression of Serca2b in the Adipose Tissue of a Cancer Cachexia Model.

Satoka Kasai, Sho Sato, Kento Namiki, Rinka Obata, Kazumi Yoshizawa.

BACKGROUND/AIM: Cancer cachexia is a complication that emerges in approximately 50-80% of patients with advanced cancer, characterized by symptoms such as lipoatrophy, skeletal muscle loss, metabolic abnormalities, and anorexia. While UCP1, a mitochondrial uncoupling protein, is implicated in lipolysis associated with cancer cachexia, the involvement of other thermogenic proteins remains unclear. In this exploratory study, we examined the expression of thermogenic genes in a mouse model of cancer cachexia.
MATERIALS AND METHODS: Tumor-bearing mice were generated by injecting Colon-26 cells (C26) into the right flank of male BALB/c mice. The body weight and temperature, tumor volume, and food intake of these mice were recorded three times a week. After 46 days of C26 administration, the adipose tissue, muscle, tumor, and blood were isolated from the mice and analyzed for thermogenic gene expression and biochemical parameters.
RESULTS: Quantitative reverse transcription PCR analysis revealed increased expression of Serca2b, a gene associated with Ucp1 independent thermogenesis, in adipose tissue of C26-bearing mice. A positive correlation between Serca2b and Ucp1 mRNA levels was observed. In addition, Serca2b expression was not responsive to norepinephrine in differentiated 3T3-L1 adipocytes.
CONCLUSION: Although the functional relevance of Serca2b up-regulation remains to be elucidated, these findings suggest a potential role for SERCA2b in adipose tissue remodeling during cachexia. This preliminary observation may serve as a foundation for future studies investigating calcium cycling and non-canonical thermogenesis in the pathophysiology of cancer cachexia.

Keywords: Cancer cachexia; Serca2b; Ucp1; cachexia; lipolysis; thermogenic gene

DOI: https://doi.org/10.21873/invivo.14177