Dataset Information

HJC0152 suppresses human non-small-cell lung cancer by inhibiting STAT3 and modulating metabolism.

ABSTRACT:

Objectives

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC.

Materials and methods

We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC-QTOF/MS was used for untargeted metabolomic relative quantitation analysis.

Results

We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways.

Conclusions

HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti-cancer effects.

SUBMITTER: Lu L

PROVIDER: S-EPMC7106968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Simple Summary We found that lncRNA Highly Accelerated Region 1A (HAR1A) was down regulated in NSCLC. Moreover, a 23-gene signature derived from HAR1A-related cancer cell survival genes could predict prognosis and chemotherapy response in LUAD. In vitro experiments indicated that HAR1A suppressed NSCLC growth by inhibiting the STAT3 signaling pathway, which was verified in the animal model. Overall, HAR1A acts as a tumor suppressor in NSCLC. The prognostic signature showed promise in predicting prognosis and chemotherapy sensitivity. Abstract It is imperative to advance the understanding of lung cancer biology. The Cancer Genome Atlas (TCGA) dataset was used for bioinformatics analysis. CCK-8 assay, flow cytometry, and western blot were performed in vitro, followed by in vivo study. We found that lncRNA Highly Accelerated Region 1A (HAR1A) is significantly downregulated in lung adenocarcinoma (LUAD) and negatively associated with prognosis. We improved the prognostic accuracy of HAR1A in LUAD by combining genes regulating cell apoptosis and cell cycle to generate a 23-gene signature. Nomogram and decision curve analysis (DCA) confirmed that the gene signature performed robustly in predicting overall survival. Gene set variation analysis (GSVA) demonstrated several significantly upregulated malignancy-related events in the high-risk group, including DNA replication, DNA repair, glycolysis, hypoxia, MYC targets v2, and mTORC1. The risk signature distinguished LUAD patients suitable for chemotherapies or targeted therapies. Additionally, the knockdown of HAR1A accelerated NSCLC cell proliferation but inhibited apoptosis and vice versa. HAR1A regulated cellular activities through the STAT3 signaling pathway. The tumor-suppressing role of HAR1A was verified in the mouse model. Overall, the gene signature was robustly predictive of prognosis and sensitivity to anti-tumor drugs. HAR1A functions as a tumor suppressor in NSCLC by regulating the STAT3 signaling pathway.