BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer.

PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, the factors influencing the efficacy of PLK1 inhibitors remain unclear. Herein, BRCA1 was identified as a key factor affecting the response of SCLC cells to BI-2536. Targeting AURKA with alisertib, at a non-toxic concentration, reduced the BI-2536-induced accumulation of BRCA1 and RAD51, leading to DNA repair defects and mitotic cell death in SCLC cells. In vivo experiments confirmed that combining BI-2536 with alisertib impaired DNA repair capacity and significantly delayed tumor growth. Additionally, GSEA analysis and loss- and gain-of-function assays demonstrated that MYC/MYCN signaling is crucial for determining the sensitivity of SCLC cells to BI-2536 and its combination with alisertib. The study further revealed a positive correlation between RAD51 expression and PLK1/AURKA expression, and a negative correlation with the IC50 values of BI-2536. Manipulating RAD51 expression significantly influenced the efficacy of BI-2536 and restored the MYC/MYCN-induced enhancement of BI-2536 sensitivity in SCLC cells. Our findings indicate that the BRCA1 and MYC/MYCN-RAD51 axes govern the response of small cell lung cancer to BI-2536 and its combination with alisertib. This study propose the combined use of BI-2536 and alisertib as a novel therapeutic strategy for the treatment of SCLC patients with MYC/MYCN activation.

Enrichment of C17:0-rich saturated fatty acids from sheep tail fat for adjuvant therapy of non-small-cell lung cancer.

Heptadecanoic acid (C17:0), an odd-chain saturated fatty acid (OCSFA) in ruminant lipid, has been demonstrated to be potential for treating cancers. Our results also showed that sheep tail fat (STF) with higher level of C17:0-containing saturated fatty acids (SFAs) whereas lower level of oleic acid (C18:1), performed remarkable inhibition against non-small-cell lung cancer (NSCLC) cells. To enrich the content of C17:0, a C17:0-rich SFA concentrate (HRSC) was prepared from STF by solvent crystallization and urea complexation methods (hexane/STF = 3.5/1, 4 °C for 8 h, and 80% ethanol/urea/free fatty acids = 8/1/1, 4 °C for 6 h). The content of C17:0 was up from 3.02 to 6.34% and the recovery was 4.17%. Biological experiments showed that HRSC exerted better antiproliferative effect against NSCLC cells. Moreover, HRSC performed enhanced inhibitory effect in A549 cell xenograft mouse model. Therefore, HRSC has the potential to be applied in adjuvant therapy for NSCLC. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01504-w.

HMGN1 loss sensitizes lung cancer cells to chemotherapy.

The high mobility group nucleosome binding (HMGN) family, constitutes a large family of non-histone protein family known to bind the acidic patch of the nucleosomes with various key cellular functions. Several studies have highlighted the pivotal roles of HMGNs in the pathogenic process of various cancer types. However, the roles of HMGN family in lung adenocarcinoma (LUAD) have not been fully elucidated. Herein, integrative analyses of multiple-omics data revealed that HMGNs frequently exhibit dysregulation in LUAD. Subsequent analysis of the clinical relevance of HMGN1 demonstrated its association with poor prognosis in LUAD and its potential as a diagnostic marker to differentiate LUAD from healthy controls. Additionally, functional enrichment analysis suggested that HMGN1 was mainly involved in DNA repair. To corroborate these findings, cellular experiments were conducted, confirming HMGN1's crucial involvement in homologous recombination repair and its potential to enhance the sensitivity of LUAD cells to standard chemotherapeutic drugs. This study proposes HMGN1 as a novel prognostic biomarker and a promising target for chemotherapy in lung adenocarcinoma.

Carbon-Encapsulated Magnetite Nanodoughnut as a NIR-II Responsive Nanozyme for Synergistic Chemodynamic-Photothermal Therapy.

Magnetite-based nanozymes have attracted great interest for catalytic cancer therapy enabled by catalyzing hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) to kill tumor cells. However, their therapeutic efficacies remain low due to insufficient •OH. Here, a light-responsive carbon-encapsulated magnetite nanodoughnuts (CEMNDs) with dual-catalytic activities for photothermal-enhanced chemodynamic therapy (CDT) is reported. The CEMNDs can accumulate in tumor and get into tumor cells and effectively act as peroxidase to convert H2 O2 to •OH that causes tumor cell death. The CEMNDs also possess intrinsic glutathione oxidase-like activity that which catalyzes the oxidation of reduced glutathione and produce lipid peroxidase for enhanced catalytic therapy. Furthermore, the CEMNDs can absorb 1064 nm light to elevate local temperature and increase release of Fe ions for photothermal therapy and enhanced CDT respectively. The in vivo experiments in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer model demonstrate excellent synergistic anti-tumor function and no measurable systemic toxicity of CEMNDs.

Corrigendum: The MYC paralog-PARP1 axis as a potential therapeutic target in MYC paralog-activated small cell lung cancer.

[This corrects the article DOI: 10.3389/fonc.2020.565820.].

Hydrophobic Carbon Dots Derived from Organic Pollutants and Applications in NIR Anticounterfeiting and Bioimaging.

In an effort to fulfill the strategy of sustainable development, Rhodamine B, a common and toxic organic pollutant in the textile industry, was reported for the first time as a single precursor to develop a kind of novel hydrophobic nitrogen-doped carbon dot (HNCD) through a green and facile one-pot solvothermal method. The HNCDs with an average size of 3.6 nm possess left and right water contact angles of 109.56° and 110.34°, respectively. The HNCDs manifest excitation wavelength-tunable and upconverted fluorescence from the ultraviolet (UV) to the near-infrared (NIR) range. Furthermore, the PEGylation of HNCDs enables them to be used as an optical marker for cell and in vivo imaging. Notably, the HNCDs with solvent-dependent fluorescence can be used for invisible inks with a wide range of light responses from UV-vis-NIR spectra. This work not only provides an innovative way to recycle chemical waste but also expands the potential application of HNCDs in NIR security printing and bioimaging.

Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors.

Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma of the lung associated with early metastasis and an exceptionally poor prognosis. Little progress has been made in developing efficacious targeted therapy for this recalcitrant disease. Herein, we showed that H3.3, encoded by two genes (H3F3A and H3F3B), was prominently overexpressed in SCLC. Darinaparsin (ZIO-101), a derivative of arsenic trioxide, dose- and time-dependently inhibited the viability of SCLC cells in an H3.3-dependent manner. More importantly, ZIO-101 treatment resulted in substantial accumulation of H3.3 and PARP1 besides induction of G2/M cell cycle arrest and apoptosis in SCLC cells. Through integrative analysis of the RNA-seq data from Cancer Cell Line Encyclopedia dataset, JNCI and Genomics of Drug Sensitivity in Cancer 2 datasets, we found that H3F3A expression was negatively correlated with the IC50 values of PARP inhibitors (PARPi). Furthermore, co-targeting H3.3 and PARP1 by ZIO-101 and BMN673/olaparib achieved synergistic growth inhibition against SCLC in vitro and in vivo. In conclusion, it is feasible to target H3.3 by ZIO-101 to potentiate the response rate of PARPi in SCLC patients.

Sheep tail fat inhibits the proliferation of non-small-cell lung cancer cells in vitro and in vivo.

Increasing evidence suggests that numerous edible oils may function as adjuvant dietary therapies to treat cancer. We previously reported that the odd-chain saturated fatty acid (OCSFA), heptadecanoic acid (C17:0), profoundly inhibits non-small-cell lung cancer (NSCLC) cell proliferation. However, the antitumor potential of edible lipids rich in C17:0 remains unclear. Here, we determined that sheep tail fat (STF) is a dietary lipid rich in C17:0 and exhibited the greatest inhibitory effect against three NSCLC cell lines (A549, PC-9, and PC-9/GR) among common dietary lipids. Cell migration experiments demonstrated that STF could significantly inhibit the wound healing capacity of three NSCLC cell lines by promoting the generation of reactive oxygen species (ROS) and subsequent cell death. Mechanistic studies showed that STF suppressed NSCLC cell growth by downregulating the Akt/S6K signaling pathway. Furthermore, administration of STF reduced tumor growth, weight, and expression of the proliferative marker Ki-67 in nude mice bearing A549 xenografts. Collectively, our data show that STF has antitumor activity against NSCLC, implying that dietary intake of C17:0-rich STF may be a potential adjuvant therapy for NSCLC.

Emerging roles of circular RNAs in gastric cancer metastasis and drug resistance.

Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis, primarily caused by metastatic lesions. Improved understanding of GC metastasis at the molecular level yields meaningful insights into potential biomarkers and therapeutic targets. Covalently closed circular RNAs (circRNAs) have emerged as crucial regulators in diverse human cancers including GC. Furthermore, accumulating evidence has demonstrated that circRNAs exhibit the dysregulated patterns in GC and have emerged as crucial regulators in GC invasion and metastasis. However, systematic knowledge regarding the involvement of circRNAs in metastatic GC remains obscure. In this review, we outline the functional circRNAs related to GC metastasis and drug resistance and discuss their underlying mechanisms, providing a comprehensive delineation of circRNA functions on metastatic GC and shedding new light on future therapeutic interventions for GC metastases.

NIR-II responsive PEGylated nickel nanoclusters for photothermal enhanced chemodynamic synergistic oncotherapy.

Rationale: All kinds of non-metal and metal-based nanozymes have been extensively explored as Fenton agents for Chemodynamic therapy (CDT). However, the low catalytic efficiency of non-metallic nanozymes and the susceptibility to oxidation and long-term toxicity of metallo-nanozymes limit their potential in CDT. Methods: In this study, we report a magneto-solvothermal method to tune the crystallinity and shape of polyethylene glycol (PEG)-ylated urchin-like nickel nanoclusters (named as 9T-PUNNC) at a high magnetic field with an intensity of 9 T for enhanced combined photothermal-chemodynamic therapy. Results: The needle-like protrusions on the surface of 9T-PUNNC can effectively increase the reception of NIR light in second NIR window (NIR-II) and transform it into local hyperthermia, achieving effective photothermal treatment. The light and heat generated by NIR-II further promotes the release of Ni2+ and improves the ability of Ni2+-mediated chemodynamic therapy (CDT). In addition, the surface coating of PEG on the surface of 9T-PUNNC improves its stability and biocompatibility of nanocrystals. In vitro and in vivo results indicate that the 9T-PUNNC could efficiently kill tumor cells (nearly 12 times more than control group) and inhibit tumor growth (nearly 9 times smaller than control group) under NIR-II irradiation through the synergistic effect of combined treatments. Conclusions: we developed a novel synthetic strategy to tune crystallinity and shape of PUNNC for enhanced NIR-II responsive photothermal conversion efficiency and accelerated acid-induced dissolution for improved ·OH generation. Such 9T-PUNNC enable a combined chemodynamic-photothermal treatment to provide superior therapeutic efficacy due to their highly synergistic effect.

CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis.

BACKGROUND: Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive. METHODS: CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments. RESULTS: We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models. CONCLUSIONS: CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.

BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.

Accumulating evidence has witnessed the Kelch-like ECH-associated protein 1(KEAP1)- nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis is the main regulatory factor of cell resistance to endogenous and exogenous oxidative assaults. However, there are few studies addressing the upstream regulatory factors of KEAP1. Herein, bioinformatic analysis suggests bromodomain-containing protein 4 (BRD4) as a potential top transcriptional regulator of KEAP1 in lung cancer. Using molecular and pharmacological approaches, we then discovered that BRD4 can directly bind to the promoter of KEAP1 to activate its transcription and down-regulate the stability of Nrf2 which in turn transcriptionally suppresses glucose-6-phosphate dehydrogenase (G6PD) in small cell lung cancer (SCLC), a highly proliferative and aggressive disease with limited treatment options. In addition, BRD4 could associate with the Nrf2 protein in a non-KEAP1-dependent manner to inhibit Nrf2 activity. Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.

Comprehensive analysis of the expression, prognosis, and immune infiltrates for CHDs in human lung cancer.

BACKGROUND: The chromodomain helicase DNA-binding (CHD) family, a group of genes that regulate nucleosome spacing and access to transcription factors, contributes to tumorigenesis in various cancers. However, the roles of CHD family members in lung cancer remain poorly understood. METHODS: We investigated the transcriptional, survival, and immune data of CHDs in patients with lung cancer from the Oncomine, UALCAN, GEPIA, Kaplan-Meier Plotter, TCGA, TIMER, cBioPortal, and CR2Cancer databases. Then, perform functional enrichment analysis of CHDs was performed using the Metascape. Finally, the expression of CHD7, CHD8 and DNA damage response genes were evaluated by quantitative real-time PCR and western blot.The effects of CHD7 or CHD8 knockdown on A549 and PC9 cells were measured in vitro by flow cytometry, cell viability and colony formation assays. RESULTS: We found that except for CHD5, nearly all members of CHDs in lung cancer showed altered expression compared with adjacent normal tissues. Moreover, the abnormal expression levels of CHDs were related to the clinical outcome of patients with lung adenocarcinoma and, to a lesser extent, patients with lung squamous cell carcinoma, which were significantly associated with the immune infiltrating levels of immune cells. Furthermore, the functions of CHDs and their neighboring genes are mainly related to DNA repair, the cell cycle, and organelle organization. Finally, cellular experiments conducted in vitro confirmed that CHD7/8 played indispensable roles in DNA damage signaling and cell cycle progression in lung adenocarcinoma cells. CONCLUSION: This study implied that CHD family members, especially in subclass III, are potential targets of precision therapy and new biomarkers for patients with lung cancer.

Mechanisms of non-coding RNA-modulated alternative splicing in cancer.

Alternative splicing (AS) is a common and pivotal process for eukaryotic gene expression regulation, which enables a precursor RNA to produce multiple transcript variants with diverse cellular functions. Aberrant AS represents a hallmark of cancer, engaged in all stages of tumorigenesis from initiation to metastasis. Accumulating pieces of evidence have revealed the involvement of non-coding RNAs (ncRNAs) in regulating AS in human cancers. In this review, we overview the underlying mechanisms of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) modulated AS at diverse levels in human cancers, and summarize their regulatory functions in tumorigenesis.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer.

Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11.

The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

CircURI1 interacts with hnRNPM to inhibit metastasis by modulating alternative splicing in gastric cancer.

Circular RNAs (circRNAs) have emerged as key regulators of human cancers, yet their modes of action in gastric cancer (GC) remain largely unknown. Here, we identified circURI1 back-spliced from exons 3 and 4 of unconventional prefoldin RPB5 interactor 1 (URI1) from circRNA profiling of five-paired human gastric and the corresponding nontumor adjacent specimens (paraGC). CircURI1 exhibits the significantly higher expression in GC compared with paraGC and inhibitory effects on cell migration and invasion in vitro and GC metastasis in vivo. Mechanistically, circURI1 directly interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to modulate alternative splicing of genes, involved in the process of cell migration, thus suppressing GC metastasis. Collectively, our study expands the current knowledge regarding the molecular mechanism of circRNA-mediated cancer metastasis via modulating alternative splicing.

Exosomal miR-92b-3p Promotes Chemoresistance of Small Cell Lung Cancer Through the PTEN/AKT Pathway.

Resistance to first-line chemotherapy drugs has become an obstacle to improving the clinical prognosis of patients with small cell lung cancer (SCLC). Exosomal microRNAs have been shown to play pro- and anti-chemoresistant roles in various cancers, but their role in SCLC chemoresistance has never been explored. In this study, we observed that the expression of exosomal miR-92b-3p was significantly increased in patients who developed chemoresistance. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-92b-3p. The PTEN/AKT regulatory network was related to miR-92b-3p-mediated cell migration and chemoresistance in vitro and in vivo in SCLC. Importantly, exosomes isolated from the conditioned medium of SBC-3 cells overexpressing miR-92b-3p could promote SCLC chemoresistance and cell migration. Furthermore, we found that plasma miR-92b-3p levels were significantly higher in patients with chemoresistant SCLC than in those with chemosensitive SCLC, but the levels were down-regulated in patients who achieved remission. Kaplan-Meier analysis showed that SCLC patients with high miR-92b-3p expression were associated with shorter progression-free survival. Overall, our results suggested that exosomal miR-92b-3p is a potential dynamic biomarker to monitor chemoresistance in SCLC and represents a promising therapeutic target for chemoresistant SCLC.