bims-necame 2025-08-10 papers

Issue of 2025–08–10
five papers selected by
Grigor Varuzhanyan, UCLA

Cell Signal. 2025 Aug 01. pii: S0898-6568(25)00449-8. [Epub ahead of print] 112034

RRM2-mediated inhibition of GPX4 ubiquitination: A novel mechanism for ferroptosis suppression and reduced cisplatin sensitivity in small cell lung cancer.

Lijie You, Zhixiong Su, Jinkun Xie, Yufang He, Shaobin Zhi, Shengzhou Zheng, Moufeng Wang, Deyu Li, Zhenhua Liu.

RRM2 is an important regulatory protein in ferroptosis pathways, but its role in small cell lung cancer (SCLC), which is characterized by rapid proliferation, frequent metastasis, and drug resistance, remains unclear. Here, we report that RRM2 is highly expressed in SCLC tissues and has excellent diagnostic potential. In vitro, Our experiments demonstrate that knockdown of RRM2 expression significantly curbs the proliferation, migration, and invasiveness of NCI-H446 and SBC-2 cells, while overexpression had the opposite effect. Furthermore, RRM2 inhibition significantly enhanced the activity of the ferroptosis pathway in SCLC cells. Additional results from mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments indicated that RRM2 directly interacts with peroxiredoxin 6 (PRDX6), and their binding inhibits the ubiquitination of the key ferroptosis protein, glutathione peroxidase 4 (GPX4), thereby inhibiting ferroptosis in SCLC. Ultimately, inhibition of RRM2 increases the cisplatin IC50 in SCLC cells, and the ferroptosis inhibitor ferrostatin-1 can reverse this effect. These findings suggest that RRM2 is involved in the regulation of GPX4 protein ubiquitination in the ferroptosis pathway, thereby inhibiting ferroptosis activity in SCLC and reducing cisplatin sensitivity. Targeting this may improve the efficacy of chemotherapy in SCLC.

Keywords: Ferroptosis; GPX4; RRM2; Resistance; Small cell lung cancer; Ubiquitination

DOI: https://doi.org/10.1016/j.cellsig.2025.112034

Cell Cycle. 2025 Aug 06. 1-16

NEDD4 is a biomarker of a poor prognosis that contributes to the progression and chemoresistance in small cell lung cancer.

Rong Gao, Yuting Bian, Yongguang Wang, Yani Zhang, Qizhi Zhu, Jinfu Nie, Zongtao Hu, Hongzhi Wang, Bo Hong.

Small cell lung cancer (SCLC) accounts for approximately 15% of primary lung carcinomas and has the poorest outcome in all subtypes of lung cancer. The major hurdle for SCLC treatment failure is resistance to platinum-based chemotherapy. Therefore, an unmet need is to discover new targets that promote SCLC progression and chemoresistance. Based on the signature of ubiquitination-related genes (URGs), differentially expressed genes between cisplatin-resistant and cisplatin-sensitive SCLC cell lines were identified using the Genomics of Drug Sensitivity in Cancer (GDSC) database. The URGs associated with the prognosis were further screened by Cox and LASSO regression analyses, as well as a Kaplan-Meier survival analysis. The E3 ligase NEDD4 was identified to be associated with cisplatin resistance, poor prognosis and tumor metastasis in SCLC. The functional enrichment analysis indicated that the functions and pathways regulated by NEDD4 were enriched in cell proliferation, cell invasion, as well as ubiquitination and PI3K-AKT pathways in SCLC. The knockdown and overexpression of NEDD4 demonstrated that NEDD4 induced the phosphorylation of AKT in SCLC cells. Cell viability, wound healing and transwell invasion assays demonstrated that NEDD4 promoted the proliferation, chemoresistance and invasion of SCLC cells. These results suggest that NEDD4 is a biomarker of a poor prognosis for SCLC, and that it promotes AKT activation, SCLC progression and chemoresistance.

Keywords: AKT; NEDD4; Small cell lung cancer; cell proliferation and invasion; chemoresistance

DOI: https://doi.org/10.1080/15384101.2025.2539657

bioRxiv. 2025 Aug 02. pii: 2025.08.01.668168. [Epub ahead of print]

Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.

Sherry X Zhou, Benjamin Madden, Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis J Maher.

BACKGROUND: The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells.
METHODS: We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition.
RESULTS: SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
CONCLUSIONS: SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.

DOI: https://doi.org/10.1101/2025.08.01.668168

J Med Life. 2025 Jun;18(6): 563-574

Magnetic resonance imaging characteristics of small cell and non-small cell lung cancer brain metastases: a retrospective study.

Daniela Pomohaci, Emilia Adriana Marciuc, Bogdan-Ionuț Dobrovăț, Mihaela-Roxana Popescu, Diana-Andreea Ilinca, Costin Chirica, Oriana-Maria Oniciuc Onicescu, Danisia Haba.

Brain metastases (BMs) from bronchopulmonary tumors are a major cause of morbidity and mortality and significantly reduce the quality of life in oncology patients. Their treatment depends on imaging features (size, number, location) and their genetic mutation subtype, small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In patients with SCLC, prophylactic whole-brain radiotherapy (WBRT) with hippocampal sparing (HS) is recommended, whereas in patients with NSCLC, systemic targeted therapy is preferred. Multiple studies have analyzed the MRI morphology of BMs from both SCLC and NSCLC to identify specific imaging characteristics that can guide the selection of appropriate treatment. However, data on lung cancer (LC) brain metastases in patients from Romania are scarce or nonexistent. Our purpose was to investigate the imaging features of both NSCLC and SCLC BMs in our population using conventional MRI protocols. We selected patients from our hospital between 2019 and 2023 who had a histopathological diagnosis of LC BMs and underwent complete MRI exams prior to any radiotherapy or surgical treatment. For every MRI feature, we created both numerical and categorical variables, which were further studied using univariate, bivariate, and multivariate analyses, as well as a machine learning algorithm. We found 62 patients (49 men, 79.03% and 13 women, 20.96%) with confirmed LC BMs, of which 53 (85.49%) had NSCLC and 7 (11.29%) had SCLC. The sites affected were the cerebral hemisphere (56.46%), the cerebellum (40.32%), and the deep nuclei (6.45%), with the latter affecting relatively younger patients (P = 0.01), most notably in the case of thalamic situs (P = 0.0001). The SCLC subgroup showed a P value of 0.025 for the number of lesions, indicating diffuse spread. The AI algorithm identified positive and negative imaging diagnostic prediction variables, including internal vascularization and the number of lesions, respectively, as well as cystic lesions and internal hemorrhage. Further multicentric studies are needed to unravel the MRI features of LC BMs.

Keywords: ADC, Apparent Diffusion Coefficient; ASC, Adenosquamous Carcinoma; BMs, Brain Metastases; CE T1-W, Contrast-Enhanced T1-Weighted; CSF, Cerebrospinal Fluid; DWI, Diffusion-Weighted Imaging; FLAIR, Fluid-Attenuated Inversion Recovery; FSPGR, Fast Spoiled Gradient-Recalled Echo; HS, Hippocampal Sparing; LC, Lung Cancer; MRI, Magnetic Resonance Imaging; NSCLC; NSCLC, Non-Small Cell Lung Cancer; SCLC; SCLC, Small Cell Lung Cancer; SRT, Stereotactic Radiotherapy; SWAN, Susceptibility-Weighted Angiography; SWI, Susceptibility-Weighted Imaging; T1-W, T1-Weighted; T2-W, T2-Weighted; WBRT, Whole-Brain Radiotherapy; brain metastases imaging; lung cancer; machine learning; magnetic resonance imaging

DOI: https://doi.org/10.25122/jml-2024-0411