bims-necame 2025-06-29 papers

Issue of 2025–06–29
five papers selected by
Grigor Varuzhanyan, UCLA

J Biochem Mol Toxicol. 2025 Jul;39(7): e70342

COTE1 Regulates AMPKα2 Deubiquitination by Targeting WWP1 Activation to Promote Proliferation and Autophagy in Small Cell Lung Cancer.

Yuhui Ma, Bin Song, Hongxia Guo, Ying Chen, Caihong Cao, Yuchen Hao, Yanmin Zheng, Xu Li.

COTE1 expression is significantly upregulated in small cell lung cancer (SCLC) tissues compared to normal lung tissues and promotes SCLC cell proliferation and migration. However, the mechanism by which COTE1 promotes these behaviors in SCLC is unclear. This study aimed to explore the role and mechanism of COTE1 in promoting the progression of SCLC and to identify potential targets for the clinical treatment of SCLC. The cells were transfected with the COTE1 overexpression plasmid or WWP1 overexpression plasmid (WT, MUT), etc., and the expression of AMPKα2 was detected via qRT-PCR and western blotting. Double immunofluorescence staining was used to observe the colocalization of COTE1 and WWP1, and protein interactions between COTE1 and WWP1 were analyzed via Co-IP. CCK-8, cell colony formation, scratch wound healing, and Transwell assays were used to assess cell proliferation, migration, and invasion. Transmission electron microscopy was used to observe cell autophagy, and western blotting was used to analyze the expression of the autophagy-related proteins AMPKα2 and p-ULK1 (Ser555). A mouse model was used to verify the effects of COTE1 on SCLC tumor growth and autophagy. We found via cell-based and In Vivo experiments that COTE1 binds to WWP1 and that high expression of COTE1 alters WWP1 expression, which in turn mediates AMPKα2 deubiquitination and promotes SCLC cell proliferation, migration, tumorigenicity, and autophagy. The overexpression of WWP1 (MUT) reversed the above effects of COTE1 on SCLC cells. In conclusion, COTE1 regulates AMPKα2 deubiquitination by targeting WWP1 activation to promote the proliferation and autophagy of SCLC cells.

Keywords: AMPKα2 ubiquitylation; COTE1; E3 ubiquitin protein ligase 1; autophagy; small cell lung cancer

DOI: https://doi.org/10.1002/jbt.70342

JCI Insight. 2025 Jun 24. pii: e190924. [Epub ahead of print]

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a Target for Antibody-Drug Conjugate Therapy.

Keisuke Shigeta, Tatsuaki Daimon, Hiroshi Hongo, Sheng-Yu Ku, Hiroki Ozawa, Naoki Haratake, Atsushi Fushimi, Ayako Nakashoji, Atrayee Bhattacharya, Shinkichi Takamori, Michihisa Kono, Masahiro Rokugo, Yuto Baba, Takeo Kosaka, Mototsugu Oya, Justine Jacobi, Mark D Long, Himisha Beltran, Donald W Kufe.

Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) invariably become resistant to treatment with targeted and cytotoxic agents. Multiple pathways have been identified as being responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC/NEPC in association with poor clinical outcomes; whereas, it is not known if the oncogenic MUC1-C/M1C protein drives treatment resistance. We demonstrated that MUC1-C is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). Our results showed that MUC1-C-mediated resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species necessary for self-renewal. Dependence of these resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state identified a potential target for treatment. In this regard, we further demonstrated that targeting MUC1-C with a M1C antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC/NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings uncovered a common MUC1-C-dependent pathway in treatment-resistant CRPC/NEPC progression and identified MUC1-C as a target for their treatment with a M1C ADC.

Keywords: Cancer; Drug therapy; Oncology; Therapeutics; Urology

DOI: https://doi.org/10.1172/jci.insight.190924

Cancers (Basel). 2025 Jun 12. pii: 1959. [Epub ahead of print]17(12):

Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.

Masuda Sharifi, Cameron M Armstrong, Shu Ning, Amy R Leslie, Zachary A Schaaf, James P Maine, Wei Lou, Pui-Kai Li, Hongyu Xu, Chengfei Liu, Allen C Gao.

BACKGROUND/OBJECTIVE: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity.
METHODS: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids.
RESULTS: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment.
CONCLUSIONS: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment.

Keywords: metabolic reprogramming; prostate cancer; steroid sulfatase; therapeutic resistance

DOI: https://doi.org/10.3390/cancers17121959

Rev Esp Med Nucl Imagen Mol (Engl Ed). 2025 Jun 20. pii: S2253-8089(25)00085-0. [Epub ahead of print] 500198

Pretreatment 18F-FDG PET/CT in predicting the survival of patients with hepatic neuroendocrine tumors.

Y Zhang, G Liu, L Zhong, B Li, Y Zhang.

OBJECTIVE: To investigate the prognostic value of pretreatment 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with hepatic neuroendocrine tumors (HNET).
METHODS: In total, 41 patients were included in this study. PET-derived metabolic parameters, including maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), of the tumors were measured. Meanwhile, clinical data, including tumor pathological findings such as the Ki-67 index were also assessed. Progression-free survival (PFS) and overall survival (OS) were evaluated. Univariate and multivariate analyses were performed to predict the prognostic value of clinical variables and PET-derived metabolic parameters in HNET patients. Correlation between PET-derived metabolic parameters and Ki-67 was estimated.
RESULTS: Univariate analyses revealed that among PET-derived metabolic parameters, SUVmax, SUVmean, and TLG were significant prognostic factors for OS (P < 0.05). Among clinical variables, the Ki-67 index and radical surgical resection were significant factors for both PFS and OS (P < 0.05). In multivariate analyses, only Ki-67 index was an independent prognostic factor for both PFS and OS (P < 0.05). Ki-67 index presented correlates with SUVmax and SUVmean (R = 0.566, P < 0.001, R = 0.493, P = 0.001, respectively).
CONCLUSIONS: In patients with HNET, the Ki-67 index was an independent prognostic factor for both PFS and OS, while SUVmax, SUVmean, and TLG measured on pretreatment 18F-FDG PET/CT scans were prognostic factors for predicting OS. Ki-67 index also presented correlates with SUVmax and SUVmean. 18F-FDG-PET may be useful as quantitative predicting prognostic imaging biomarkers, especially in poorly differentiated HNET.

Keywords: 2-[(18)F]-fluoro-2-deoxy-D-glucose; 2-[(18)F]-fluoro-2-desoxid-glucosa; Hepatic neuroendocrine tumors; Positron emission tomography/computed tomography (PET/CT); Tomografía por emisión de positrones/tomografía computarizada (PET/CT); Tumores neuroendocrinos hepáticos primarios

DOI: https://doi.org/10.1016/j.remnie.2025.500198

Adv Sci (Weinh). 2025 Jun 24. e13608

The LDH-H3K18La-Nur77 Axis Potentiates Immune Escape in Small Cell Lung Cancer.

Xiaoling Shang, Bo Cheng, Chenyue Zhang, Chenglong Zhao, Ruiqing Wang, Xun Zhang, Dizhi Jiang, Xinyu Zhang, Xinyue Ma, Hongyuan Mao, Zerun Li, Chenhan Huang, Tianzi Wang, Kaiyue Guo, Liwen Wang, Ning Tang, Haiyong Wang.

Small cell lung cancer (SCLC) remains a therapeutic challenge due to its aggressive nature and limited response to immunotherapy. This study identifies lactate-induced histone lactylation as a novel epigenetic mechanism in SCLC, contributing to immune escape and poor therapeutic outcomes. By identifying the LDH-H3K18La-Nur77 axis, new insights into the metabolic regulation of immune responses in SCLC are offered. Multi-omics analysis, including metabolomics and TCR sequencing, is used to compare serum samples and immune cell profiles from SCLC patients. Data from Shanzhong cohort (n = 222), along with a validation cohort from the IMpower133 study (n = 264), demonstrates that LDH levels are associated with poorer outcomes following immunotherapy. ChIP-qPCR and luciferase reporter assays reveal that lactate-induced histone lactylation at H3K18La induces transcriptional activation of Nur77 in naïve CD8+ T cells, leading to tonic TCR signaling, which impairs antigen recognition and prevents effective anti-tumor activity. In preclinical SCLC models, lactate inhibition reduces Nur77 expression, restores T cell function, and enhances the efficacy of PD-1 blockade, leading to a decreased tumor burden and improved survival. This study uncovers a novel mechanism of immune escape in SCLC through lactate-driven histone lactylation and provides the first evidence that targeting lactate metabolism can enhance immunotherapy effectiveness.

Keywords: H3K18La; Nur77; SCLC; lactate; naïve CD8+T cells

DOI: https://doi.org/10.1002/advs.202413608