bims-necame 2026-01-04 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–01–04
eight papers selected by
Grigor Varuzhanyan, UCLA

Asparagine synthetase (ASNS) Drives Tumorigenicity in Small Cell Lung Cancer.
The impact of targeting TRAF2 and NCK-interacting protein kinase (TNIK) on anti-tumor effect and tumor immune environment in c-MYC-high small cell lung cancer.
Integrated methylome analysis identifies an epigenetically silenced tumor suppressor RASA4 in small cell lung cancer.
Autophagy-Targeting Stapled Peptide Utilizes Macropinocytosis for Cell Entry to Potentiate Anti-Proliferative Autosis in Small-Cell Lung Cancer.
Adenylate Kinase 2 Promotes Tumor Progression in Small-cell Lung Cancer via PI3K/AKT/mTOR Signaling.
The Olive Phenolic S-(-)-Oleocanthal as a Novel Intervention for Neuroendocrine Prostate Cancers: Therapeutic and Molecular Insights.
Lactate represses MHC-I antigen presentation via H4K5 lactylation-PRC2 in small cell lung cancer subtype A.
Sestrin3 confers resistance to recombinant human arginase in small cell lung cancer by activating Akt/mTOR/ASS1 axis.

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
J Thorac Oncol. 2025 Dec 26. pii: S1556-0864(25)03066-7. [Epub ahead of print]

The impact of targeting TRAF2 and NCK-interacting protein kinase (TNIK) on anti-tumor effect and tumor immune environment in c-MYC-high small cell lung cancer.

Azusa Tanimoto, Kavya Ramkumar, C Allison Stewart, Bingnan Zhang, Kyle Concannon, Robert J Cardnell, Li Shen, Qi Wang, Jing Wang, Carl M Gay, Lauren Averett Byers.

INTRODUCTION: Wnt/β-catenin signaling pathway activation contributes to tumorigenesis and chemo-resistance in small cell lung cancer (SCLC), yet clinical attempts to target this pathway have been unsuccessful. TRAF2 and NCK-interacting protein kinase (TNIK), an essential nuclear activator of Wnt/β-catenin target genes, has not yet been validated as a viable therapeutic target in SCLC. Here, we validated that TNIK inhibition is a promising approach for personalized anti-cancer therapy in SCLC.
METHODS: We correlated the IC50 values of a TNIK inhibitor, NCB-0846 with proteomic profiling (Reverse Phase Protein Array, RPPA) data across 28 SCLC cell lines. Cytokine array analysis was performed to quantify changes in 105 cytokines following TNIK inhibitor treatment.
RESULTS: We identified c-MYC expression as a top candidate marker of TNIK inhibition response. In xenograft models of c-MYChigh SCLC, TNIK inhibition led to suppression of tumor growth and a decrease in c-MYC expression. In the clinically aggressive POU2F3 expressing subtype of SCLC, the TNIK inhibitor showed anti-tumor effect by decreasing SOX9 in addition to c-MYC. Furthermore, TNIK inhibition suppressed the production of the immunosuppressive chemokine CCL2 by attenuating its transcription factor FOXK1 in c-MYChigh SCLC cells. Combination of TNIK inhibition and an anti-PD-L1 antibody resulted in greater efficacy and reduced infiltration of immunosuppressive cells infiltration compared with each monotherapy in immunocompetent SCLC in vivo models.
CONCLUSIONS: TNIK inhibition is more effective in c-MYChigh SCLC, acting through downregulation of c-MYC levels. It also decreases the production of CCL2, supporting the rationale for combination therapy with immune checkpoint inhibitors in c-MYChigh SCLC.

DOI: https://doi.org/10.1016/j.jtho.2025.12.102
Commun Biol. 2025 Dec 31.

Integrated methylome analysis identifies an epigenetically silenced tumor suppressor RASA4 in small cell lung cancer.

Meng Fu, Qizhi Zhu, Jian Qi, Xiaopeng Zhang, Zhipeng Wang, Jialiang Wang, Xiang Huang, Zongtao Hu, Wei Wang, Bo Hong, Hongzhi Wang.

Small cell lung cancer (SCLC) is highly lethal, often developing rapid chemo-resistance and progression after initial response to platinum-based chemotherapy. The role of DNA methylation in driving this progression remains poorly understood. Here, genome-wide methylation profiling via methylated DNA immuno-precipitation sequencing (MeDIP-seq) reveals hypermethylated and hypomethylated regions in both SCLC tissue DNA and plasma cell free DNA (cfDNA). A hypermethylated region in the promoter of RASA4 gene, common to SCLC tumor DNA and progression-associated cfDNA, is identified. Pharmacologic and, more specifically, targeted demethylation reactivate RASA4 expression in SCLC. The down-regulation of RASA4, a negative regulator of Ras signal, leads to the activation of Ras-MAPK pathway in SCLC. RASA4 overexpression inhibits SCLC growth, invasion and chemo-resistance, whereas its knockdown promotes these malignant phenotypes by enhancing epithelial-mesenchymal transition (EMT) and stemness. We further demonstrate that RASA4 negatively regulates the EMT-related protein SERPINE2, and directly interacts with it. Immunohistochemistry analysis of clinical specimens validates that RASA4 is significantly down-regulated in SCLC tumors, and its low expression correlates with SCLC patients' poor survival. Taken together, the epigenetic silencing of RASA4 drives SCLC progression through the induction of EMT and stemness. Our findings underscore the potential of RASA4 as a diagnostic biomarker and therapeutic target.

DOI: https://doi.org/10.1038/s42003-025-09440-7
Pharmaceutics. 2025 Nov 26. pii: 1521. [Epub ahead of print]17(12):

Autophagy-Targeting Stapled Peptide Utilizes Macropinocytosis for Cell Entry to Potentiate Anti-Proliferative Autosis in Small-Cell Lung Cancer.

Jingyi Chen, Shan Gao, Xiaozhe Zhang, Na Li, Yingting Yu, Lei Wang, Yu Feng, Yuanzhi Lao, Yanxiang Zhao.

  Background: Small-cell lung cancer (SCLC) is an aggressive malignancy marked by rapid progression, early metastasis, and frequent relapse despite chemotherapy. Due to its genetic complexity, targeted therapies have limited success. Autophagy, a lysosome-dependent cellular degradation process, plays a key role in SCLC, yet effective autophagy-targeting strategies are lacking. This study evaluates Tat-SP4, an autophagy-targeting stapled peptide, for its anti-proliferative effects in SCLC. Method: We assessed Tat-SP4's impact on autophagy in SCLC cells by measuring p62 and LC3 levels. Mitochondrial function was evaluated via mitochondrial membrane potential (Δψm) and oxygen consumption rate (OCR). Anti-proliferative effects were determined using cell viability assays in vitro and xenograft models in vivo. Cellular uptake mechanisms were investigated using Ca2+ imaging and pharmacological inhibitors. Result: Tat-SP4 induced a strong autophagic response and triggered autosis, a form of autophagy-dependent necrotic cell death, impairing SCLC cell proliferation. It also caused mitochondrial dysfunction with impaired oxidative phosphorylation (OXPHOS). Tat-SP4 entered cells predominantly via macropinocytosis, triggering extracellular Ca2+ influx measurable by live-cell imaging. Digoxin, an Na+, K+-ATPase inhibitor, partially reversed the effect of Tat-SP4 on Ca2+ influx, cell death, and OXPHOS activity. Lastly, Tat-SP4 inhibited tumor growth in a xenograft-based animal model for SCLC. Conclusions: The autophagy-targeting stapled peptide Tat-SP4 inhibited the proliferation of SCLC cells in vitro and inhibited the growth of the SCLC tumor in vivo. Macropinocytosis facilitates cell entry for Tat-SP4, which can be monitored by influx of extracellular Ca2+. By exploiting macropinocytosis for cell entry and converting the pro-survival autophagy process into a death pathway, Tat-SP4 represents a novel therapeutic strategy against SCLC.

Keywords:  autophagy; autosis; macropinocytosis; small cell lung cancer

DOI:  https://doi.org/10.3390/pharmaceutics17121521
Anticancer Res. 2026 Jan;46(1): 205-212

Adenylate Kinase 2 Promotes Tumor Progression in Small-cell Lung Cancer via PI3K/AKT/mTOR Signaling.

Hong-Beum Kim, Yong Sub Na, Seong-Hun Kim, Hee-Jeong Lee, Sang-Gon Park.

   BACKGROUND/AIM: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic progress. Adenylate kinase 2 (AK2), a mitochondrial isoenzyme involved in nucleotide metabolism and apoptosis regulation, has been implicated in tumorigenesis, but its role in SCLC remains undefined. This study aimed to investigate the oncogenic function of AK2 in SCLC and its regulatory mechanism through the PI3K/AKT/mTOR signaling pathway.
MATERIALS AND METHODS: AK2 expression was analyzed using the GSE60052 dataset and validated using western blotting in SCLC cell lines. Functional assays, including MTT, proliferation, colony formation, and phospho-kinase array profiling, were performed following siRNA-mediated AK2 knockdown in HCC-33 and H417 cells. Western blotting was used to confirm pathway alterations. In vivo tumorigenicity was assessed in xenograft models.
RESULTS: AK2 was markedly up-regulated in SCLC tissues and cell lines. Silencing AK2 significantly inhibited proliferation and clonogenic growth of SCLC cells and reduced tumorigenicity in vivo. Phospho-kinase analysis and western blot validation demonstrated that AK2 knockdown altered phosphorylation of key components in the PI3K/AKT/mTOR pathway, including AKT and mTOR.
CONCLUSION: AK2 acts as an oncogenic driver in SCLC, promoting tumor progression through PI3K/AKT/mTOR signaling. Targeting AK2 may represent a novel therapeutic strategy and predictive biomarker in SCLC management.

Keywords:  PI3K/AKT/mTOR signaling; Small cell lung cancer; adenylate kinase 2(AK2); tumor progression

DOI:  https://doi.org/10.21873/anticanres.17935
Nutrients. 2025 Dec 17. pii: 3947. [Epub ahead of print]17(24):

The Olive Phenolic S-(-)-Oleocanthal as a Novel Intervention for Neuroendocrine Prostate Cancers: Therapeutic and Molecular Insights.

Md Towhidul Islam Tarun, Hassan Y Ebrahim, Dalal Dawud, Zakaria Y Abd Elmageed, Eva Corey, Khalid A El Sayed.

  Background/Objectives. Prostate cancer (PCa) is among the leading causes of death from cancer in men. Frequent use of androgen receptor inhibitors induces PCa transdifferentiation, leading to poorly differentiated neuroendocrine PCa (NEPC). ROR2 is critical for NEPC pathogenesis by activating ASCL1, promoting lineage plasticity. Protein lysine methylation mediated by N-lysine methyltransferases SMYD2 and its downstream effector EZH2 upregulates the NEPC marker ASCL1 and enhances c-MET signaling, promoting PCa aggression. Epidemiological studies suggest a lower incidence of certain malignancies in Mediterranean populations due to their intake of an olive-phenolics-rich diet. Methods. Cell viability, gene knockdown, and immunoblotting were used for in vitro analyses. A nude mouse NEPC xenograft model evaluated the anti-tumor efficacy of purified and crude oleocanthal. Xenograft tumors were subjected to RNA-seq, qPCR, and Western blot analyses, with clinical validation performed using tissue microarrays. Results. A tissue microarray analysis showed that SMYD2 expression was significantly elevated in PCa tissues with higher IHS versus normal prostate tissue cores. The olive phenolic S-(-)-oleocanthal (OC) suppressed the de novo NEPC NCI-H660 cells proliferation. Male athymic nude mice xenografted with the NCI-H660-Luc cells were used to assess OC effects on de novo NEPC progression and recurrence. Male NSG mice transplanted with LuCaP 93 PDX tumor tissues generated a heterogeneous in vivo model used to assess OC effects against t-NEPC progression. Daily oral 10 mg/kg OC administration significantly suppressed the NCI-H660-Luc tumor progression and locoregional recurrence after primary tumor surgical excision. OC treatments effectively suppressed the progression of LuCaP 93 PDX tumors. OC-treated tumors revealed downregulation of ROR2, ASCL1, SMYD2, and EZH2, as well as activated c-MET levels versus the placebo control. RNA sequencing of the collected treated NEPC tumors showed that OC disrupted NEPC splicing, translation, growth factor signaling, and neuronal differentiation. Conclusions. This study's findings validate OC as a novel lead entity for NEPC management by targeting the ROR2-ASCL1-SMYD2-EZH2-c-MET axis.

Keywords:  LuCaP 93 Patient-Derived Xenograft; RNA sequencing; ROR2-ASCL1-SMYD2-EZH2-c-MET axis; S–(–)–oleocanthal; de novo and treatment-induced neuroendocrine prostate cancer; recurrence

DOI:  https://doi.org/10.3390/nu17243947
Int Immunopharmacol. 2025 Dec 29. pii: S1567-5769(25)02114-9. [Epub ahead of print]170 116125

Lactate represses MHC-I antigen presentation via H4K5 lactylation-PRC2 in small cell lung cancer subtype A.

Yifan Cai, Xinyue Li, Shuang Zhu, Hao Wu, Jun Nie, Fang Huang.

   OBJECTIVE: Small cell lung cancer (SCLC) responds poorly to immunotherapy. This study investigates how glycolytic reprogramming drives immune evasion in SCLC by epigenetically suppressing MHC-I mediated antigen presentation.
METHODS AND RESULTS: Bioinformatic and murine model studies confirmed SCLC with high ASCL1 expression (SCLC-A) as an immunologically "cold" subtype, exhibiting elevated glycolytic activity that was inversely correlated with profoundly suppressed MHC-I pathway activity. High LDHA expression was associated with advanced disease stage and shorter overall survival in patients. In vitro and in vivo studies demonstrated that LDHA knockdown or its pharmacological inhibition restored the expression of MHC-I (H2Db/H2Kb; HLA-ABC) and β2-microglobulin (B2M). This promoted antitumor immunity, increasing CD4+ and CD8+ T cell infiltration and inhibiting tumor growth. These effects were reversed by sodium lactate, confirming lactate as the key metabolite. Mechanistically, LDHA-derived lactate promoted histone H4K5 lactylation (H4K5la) via the acyltransferase P300. This modification enriched at the promoters of the PRC2 core subunits EZH2 and EED, enhancing their transcription and thus PRC2-mediated silencing of MHC-I. The restoration of MHC-I following LDHA loss was mediated by a parallel H4K5la-PRC2 regulatory axis independent of the canonical NLRC5 pathway. Combination therapy with LDHA inhibitor FX11 and anti-PD-1 antibody synergistically inhibited tumor growth and enhanced immune activation with a favorable safety profile.
CONCLUSION: Our work uncovers the LDHA-H4K5la-PRC2 axis as a novel metabolic-epigenetic pathway that suppresses antigen presentation in SCLC-A. Targeting this axis with an LDHA inhibitor effectively sensitizes SCLC to anti-PD-1 therapy, representing a promising strategy to overcome immunotherapy resistance.

Keywords:  Histone lactylation (H4K5la); Immunotherapy; LDHA; MHC-I antigen presentation; PRC2; Small cell lung cancer subtype A (SCLC-A)

DOI:  https://doi.org/10.1016/j.intimp.2025.116125
PLoS One. 2025 ;20(12): e0338802

Sestrin3 confers resistance to recombinant human arginase in small cell lung cancer by activating Akt/mTOR/ASS1 axis.

Zhongqiang Zhang, Zizhe Lin, Weishan Li, Binxiong Chen, Yueming Liu, Hanchao Gao, Shi Xu.

Drug resistance is a major obstacle in the clinical management of small cell lung cancer (SCLC), we have proved the promising anticancer effect of recombinant human arginase (rhArg, BCT-100) in SCLC in vitro and in vivo. In order to promote the clinical application of recombinant human arginase, it is necessary to explore the underlying resistant mechanisms of BCT-100 in SCLC. Here, we cultured and obtained the acquired drug-resistant SCLC cell line (H446-BR), which displayed different cellular phenotypes (enhanced migration ability) compared with the parental cell line (H446). sestrin3 (SESN3) was confirmed with high expression in resistant cell line. Knockdown SESN3 could re-sensitize resistant cells to BCT-100 treatment and reverse the aggressive feature of H446-BR. The Akt-mTOR signal pathway and ASS1, which were highly expressed in resistant cells, were down-regulated after silencing SESN3. MK-2206 and rapamycin suppressed the expression of ASS1 in H446-BR cell. In xenograft model, BCT-100 has little anti-tumor effect on H446-BR compared with H446 as well as H446-BR silenced sestrin3. Collectively, these results elucidate SESN3 plays an essential role in resistant mechanism, which will provide a valuable source of information for translational research.

DOI: https://doi.org/10.1371/journal.pone.0338802