bims-necame 2025-04-20 papers

iScience. 2025 Apr 18. 28(4): 112219

Supinoxin blocks small cell lung cancer progression by inhibiting mitochondrial respiration through DDX5.

Subhadeep Das, Maria P Zea, Matthew P Russon, Zheng Xing, Sandra Torregrosa-Allen, Heidi E Cervantes, Haley Anne Harper, Bennett D Elzey, Elizabeth J Tran.

DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR, respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.

Keywords: Cancer; Molecular biology; Transcriptomics

DOI: https://doi.org/10.1016/j.isci.2025.112219

Cancer Cell. 2025 Apr 15. pii: S1535-6108(25)00128-X. [Epub ahead of print]

Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation.

Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.

Keywords: RNA protein interactions; circular RNA; lineage plasticity; neuroedocrine prostate cancer; noncoding RNA; small cell lung cancer; transcription factors

DOI: https://doi.org/10.1016/j.ccell.2025.03.027

J Clin Invest. 2025 Apr 15. pii: e191687. [Epub ahead of print]135(8):

Serotonin sets up neutrophil extracellular traps to promote neuroendocrine prostate cancer metastasis in the liver.

Dean G Tang.

Castration-resistant prostate cancer frequently metastasizes to the liver, and prostate cancer liver metastases often present a neuroendocrine phenotype (i.e., neuroendocrine prostate cancer [NEPC]), but the underlying molecular underpinnings remain unclear. In this issue of the JCI, Liu et al. demonstrate that the neurotransmitter serotonin (also known as 5-hydroxytryptamine), produced by NEPC cells, gained access to and activated neutrophils by modifying histone 3 (H3) to form neutrophil extracellular traps, which in turn promoted NEPC macrometastases in the liver. The study suggests that blocking serotonin transport to neutrophils and inhibiting the enzymes that catalyze serotonin-mediated H3 modifications may represent alternative approaches to treating prostate cancer liver metastases.

DOI: https://doi.org/10.1172/JCI191687