ABSTRACT
Colorectal cancer (CRC) is a prevalent form of gastrointestinal malignancy with challenges in chemotherapy resistance and side effects. Effective and low toxic drugs for CRC treatment are urgently needed. Ferroptosis is a novel mode of cell death, which has garnered attention for its therapeutic potential against cancer. Baicalein (5, 6, 7-trihydroxyflavone) is the primary flavone extracted from the dried roots of Scutellaria baicalensis that exhibits anticancer effects against several malignancies including CRC. In this study, we investigated whether baicalein induced ferroptosis in CRC cells. We showed that baicalein (1-64 µM) dose-dependently inhibited the viability of human CRC lines HCT116 and DLD1. Co-treatment with the ferroptosis inhibitor liproxstatin-1 (1 µM) significantly mitigated baicalein-induced CRC cell death, whereas autophagy inhibitor chloroquine (25 µM), necroptosis inhibitor necrostatin-1 (10 µM), or pan-caspase inhibitor Z-VAD-FMK (10 µM) did not rescue baicalein-induced CRC cell death. RNA-seq analysis confirmed that the inhibitory effect of baicalein on CRC cells is associated with ferroptosis induction. We revealed that baicalein (7.5-30 µM) dose-dependently decreased the expression levels of GPX4, key regulator of ferroptosis, in HCT116 and DLD1 cells by blocking janus kinase 2 (JAK2)/STAT3 signaling pathway via direct interaction with JAK2, ultimately leading to ferroptosis in CRC cells. In a CRC xenograft mouse model, administration of baicalein (10, 20 mg/kg, i.g., every two days for two weeks) dose-dependently inhibited the tumor growth with significant ferroptosis induced by inhibiting the JAK2/STAT3/GPX4 axis in tumor tissue. This study demonstrates that ferroptosis contributes to baicalein-induced anti-CRC activity through blockade of the JAK2/STAT3/GPX4 signaling pathway, which provides evidence for the therapeutic application of baicalein against CRC.
ABSTRACT
Metastasis is the main cause of mortality in patients with cancer. Epithelial-mesenchymal transition (EMT), a crucial process in cancer metastasis, is an established target for antimetastatic drug development. LFG-500, a novel synthetic flavonoid, has been revealed as a potential antitumor agent owing to its various activities, including modulation of EMT in the inflammatory microenvironment. Here, using a transforming growth factor beta (TGF-ß)-induced EMT models, we found that LFG-500 inhibited EMT-associated migration and invasion in human breast cancer, MCF-7, and lung adenocarcinoma, A549, cell lines, consistent with the observed downregulation of YAP activity. Further studies demonstrated that LGF-500-induced suppression of YAP activation was mediated by integrin-linked kinase (ILK), suggesting that the ILK/YAP axis might be feasible target for anti-EMT and antimetastatic treatments, which was verified by a correlation analysis with clinical data and tumor specimens. Hence, our data support the use of LGF-500 as an antimetastatic drug in cancer therapy and provide evidence that the ILK/YAP axis is a feasible biomarker of cancer progression and a promising target for repression of EMT and metastasis in cancer therapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Epithelial-Mesenchymal Transition/drug effects , Flavonoids/administration & dosage , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , YAP-Signaling Proteins/antagonists & inhibitors , A549 Cells , Animals , Cell Movement/drug effects , Cell Movement/physiology , Dose-Response Relationship, Drug , Drug Delivery Systems/methods , Epithelial-Mesenchymal Transition/physiology , Female , Hep G2 Cells , Humans , MCF-7 Cells , Male , Mice , Mice, Transgenic , Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/physiology , YAP-Signaling Proteins/metabolismABSTRACT
Based on the relevant studies of land use environmental impacts and the characteristics of urban land use, a conceptual model on the assessment of land use environmental impacts in urban built-up area was established. This model grouped the land use environmental impacts in built-up area into four basic processes, i. e., detailization, abstractization, matching, and evaluation. A case study was conducted in the main built-up area of Nanchang City, with noise, smell, dust, and hazard as the impact factors. In the test area, noise had a widespread impact, its impacting area accounting for 59% of the total, smell and dust impacts centralized in the east and south parts, while hazard impact was centralized in the southeast part, an industrial area. This assessment model of four basic processes was practical, and could provide basis for the decision-making of urban land use management and planning.
