Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for effective therapeutic agents. Natural products represent an important source of novel anticancer compounds. In this study, we investigated the anti-NSCLC activity of 10,11-dehydrocurvularin (DCV), a fungal-derived macrolide. DCV potently inhibited the proliferation of NSCLC cell lines (A549 and NCI-H1703) in a dose-dependent manner, with IC₅₀ values of 7.92 μM and 5.33 μM, respectively. Furthermore, DCV (30 mg/kg) markedly suppressed tumor growth in A549 xenograft models without causing evident systemic toxicity, as evidenced by reduced tumor volume and weight, with no significant changes in body weight or organ histopathology. Through RNA-seq, drug affinity responsive target stability, and molecular docking analyses, we identified phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a key enzyme in de novo purine biosynthesis, as a direct binding target of DCV. Mechanistically, DCV engagement promoted PAICS protein downregulation and disrupted nucleotide metabolism, leading sequentially to mitochondrial dysfunction, reactive oxygen species accumulation, DNA damage, and cell cycle arrest, ultimately triggering intrinsic apoptosis. Collectively, these findings uncover the anti-NSCLC efficacy and mechanism of DCV, positioning it as a promising natural bioactive lead for subsequent pharmacological development against lung cancer.
Abstract Purpose The radiation‐induced bystander effect (RIBE) refers to biological responses in non‐irradiated cells exposed to signals from irradiated cells and may contribute to tumor control during radiotherapy. Periodic dose heterogeneity caused by the thread effect of helical tomotherapy (TOMO) may favor RIBE, but the underlying intercellular mechanisms remain unclear. This study investigated exosome‐mediated bystander responses and their molecular and clinical relevance in cervical cancer. Methods Thread effect and uniform TOMO irradiation plans were established, and their effects on cervical cancer cell viability, DNA damage, apoptosis, and cell‐cycle progression were compared. Cell‐mixture, conditioned‐medium transfer, exosome‐depletion, and xenograft models were used to characterize RIBE. Proteomic analysis and exosomal miRNA sequencing identified candidate regulators. Gain‐ and loss‐of‐function experiments evaluated the effects of hnRNPA1 on exosomal miRNA levels and bystander tumor suppression. Dual‐luciferase and rescue assays validated the miR‐27a‐3p/HIPK2 relationship. Survival associations were assessed in 218 TOMO‐treated patients and an independent TCGA‐CESC cohort. Results The thread plan produced growth‐inhibitory effects consistent with a contribution of RIBE. Co‑culture with irradiated tumor cells significantly increased DNA damage and inhibited cell proliferation in non‑irradiated bystander cells. Exosome‐depleted conditioned medium largely lost its growth‐inhibitory activity, supporting exosomes as major mediators of this bystander response. Irradiation did not markedly alter exosome yield, size, morphology, or cellular uptake but reduced exosomal hnRNPA1 levels. hnRNPA1 overexpression attenuated exosome‐mediated growth inhibition. Conversely, hnRNPA1 depletion decreased exosomal miR‐27a‐3p levels and enhanced tumor suppression. Target prediction and pathway enrichment prioritized miR‐27a‐3p for functional validation. miR‐27a‐3p directly targeted the HIPK2 3′ untranslated region and promoted cervical cancer cell proliferation, while HIPK2 overexpression counteracted this effect. These findings support an hnRNPA1/miR‐27a‐3p/HIPK2 regulatory model in which radiation‐induced loss of exosomal hnRNPA1 reduces exosomal miR‐27a‐3p, relieves HIPK2 repression, and enhances tumor‐inhibitory bystander responses. High hnRNPA1 expression was associated with shorter OS and PFS in the TOMO‐treated cohort and with adverse survival outcomes in the TCGA‐CESC cohort. High HIPK2 expression was associated with longer OS and PFS in the TOMO‐treated cohort. Conclusion Tumor cell‐derived exosomes are major mediators of cervical cancer RIBE. Radiation‐induced reduction of exosomal hnRNPA1 may enhance tumor‐inhibitory bystander responses through the miR‐27a‐3p/HIPK2 axis. This pathway represents a candidate target for modulating RIBE, while the prognostic utility of hnRNPA1 warrants validation in independent radiotherapy cohorts.
Mengying Yang, Ping Huang, Yunrui Song et al.· Precision Radiation Oncology· 0 citations