Lycorine, a naturally occurring compound extracted from the Amaryllidaceae plant family, has been reported to exhibit antitumour activity in various cancer cell types. In the present study, we investigated the molecular mechanisms underlying lycorine-induced apoptosis in hepatoblastoma HepG2 cells. We found that lycorine induced mitochondria-dependent apoptosis in HepG2 cells accompanied by mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (MMP) loss, adenosine triphosphate (ATP) depletion, Ca2+ and cytochrome c (Cyto C) release, as well as caspase activation. Furthermore, we found Rho associated coiled-coil containing protein kinase 1 (ROCK1) cleavage/activation played a critical role in lycorine-induced mitochondrial apoptosis. In addition, the ROCK inhibitor Y-27632 was employed, and we found that co-treatment with Y-27632 partly attenuated lycorine-induced ROCK1 activation and mitochondrial apoptosis. Meanwhile, an in vivo study revealed that lycorine inhibited tumour growth and induced apoptosis in a HepG2 xenograft mouse model in association with ROCK1 activation. Taken together, all these findings suggested that lycorine induced mitochondria-dependent apoptosis through ROCK1 activation in HepG2 cells, and this may be a theoretical basis for lycorine's anticancer effects.
Background: The PITX gene family, comprising PITX1, PITX2, and PITX3, is critical in organogenesis and has been evolutionary conserved in animals. PITX genes are associated with the advanced progression and poor prognosis of multiple cancers. However, the relationship between the PITX genes and head and neck squamous cell carcinoma (HNSC) has not been reported. Methods: We used data from The Cancer Genome Atlas (TCGA) to analyze the association between PITX mRNA expression and clinicopathological parameters of patients with HNSC. The prognostic value of PITX genes was evaluated using the Kaplan-Meier plotter. Multivariate Cox analysis was used to screen out prognosis-associated genes to identify better prognostic indicators. The potential roles of PITX1 and PITX2 in HNSC prognosis were investigated using the protein-protein interaction (PPI) network, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The correlation between PITX1 and PITX2 expression or methylation and immune cell infiltration was evaluated using the tumor-immune system interaction database (TISIDB). MethSurv was used to identify DNA methylation and its effect on HNSC prognosis. Results:PITX genes expression was correlated with different cancers. PITX1 and PITX2 expression was lower in the patients with HNSC. In HNSC, PITX1 expression was significantly related to the clinical stage, histologic grade, and N stage, while PITX2 expression was only significantly related to the histologic grade. The high expression of PITX3 was significantly related to the histologic grade, T stage, and N stage. Survival analysis revealed that PITX genes had prognostic value in HNSC, which was supported by multivariate Cox analysis. PPI network and enrichment analysis showed that the genes interacting with PITX1 and PITX2 belonged predominantly to signaling pathways associated with DNA binding and transcription. Of the CpG DNA methylation sites in PITX1 and PITX2, 28 and 22 were related to the prognosis of HNSC, respectively. Additionally, PITX1 and PITX2 expression and methylation was associated with tumor-infiltrating lymphocytes (TILs). Conclusion: The PITX genes were differentially expressed in patients with HNSC, highlighting their essential role in DNA methylation and tumor-infiltrating immune cell regulation, as well as overall prognostic value in HNSC.
Studies have shown that nifedipine, an anti-hypertensive drug, protects against atherosclerotic progression, but the underlying mechanisms remain elusive. Oxidized low-density lipoprotein (ox-LDL) is critically implicated in macrophage lipid deposition seen in atherosclerosis. In this study, we examined the effects of nifedipine on some ox-LDL-associated changes in human blood-derived macrophages. We isolated monocytes from normal human blood and differentiated them into macrophages. We then treated these human macrophages with ox-LDL and/or nifedipine, and examined lipid accumulation and expression levels of two scavenge receptors CD36 and SR-A as well as a protein kinase PKC-θ. Nifedipine treatment substantially reduced lipid accumulation and the expression of CD36, SR-A, and protein kinase C (PKC)-θ in human macrophages treated with ox-LDL. Silencing of PKC-θ using siRNA also reduced the expression of CD36 and SR-A in these cells. Our results thus suggest that nifedipine may inhibit atherosclerosis by reducing ox-LDL-induced lipid deposition through suppression of the CD36/SR-A-mediated uptake of ox-LDL by macrophages via a PKC-θ-dependent mechanism.
Rho‑associated protein kinase 1 (ROCK1), a member of the ROCK family, serves an important function in cell migration and invasion in neoplasms. ROCK1 has been found to be overexpressed in several types of cancers. However, the role of ROCK1 in non‑small‑cell lung cancer (NSCLC) is poorly understood. In the present study, ROCK1 was found to be overexpressed in NSCLC cells and tissues, and it was associated with poor survival of NSCLC patients. Subsequently, ROCK1 knockdown NSCLC cell lines were established using shRNA. ROCK1 knockdown significantly reduced the migration and invasion ability in the cell monolayer scratching and Transwell assays. ROCK1 knockdown was also found to markedly inhibit cell adhesion ability. Moreover, the phosphorylation of focal adhesion kinase (FAK) was inhibited by ROCK1 knockdown, reducing NSCLC cell migration and invasion ability. This mechanistic study revealed that ROCK1 significantly enhanced cell migration and invasion by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3‑kinase (PI3K)/FAK pathway. More importantly, the interruption of the PTEN/PI3K/FAK pathway markedly rescued the inhibition of cell migration and invasion mediated by ROCK1 knockdown. Taken together, these results suggest a novel role for ROCK1 in cell migration and invasion by inhibiting cell adhesion ability, and indicate that ROCK1 may be of value as a therapeutic target for the treatment of NSCLC.
Abstract IR ‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR ‐783 has not been well demonstrated. In this study, we showed that IR ‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA ‐ MB ‐231 cells to IR ‐783 resulted in the loss of mitochondrial membrane potential ( MMP ), adenosine triphosphate ( ATP ) depletion, mitochondrial permeability transition pore ( mPTP ) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR ‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor ( MFF ) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 ( OPA 1). Moreover, knockdown of Drp1 markedly blocked IR ‐783‐mediated mitochondrial fission, loss of MMP , ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR ‐783 markedly inhibited tumour growth and induced apoptosis in an MDA ‐ MB ‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR ‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR ‐783 and provided novel perspectives for the application of IR ‐783 in the treatment of breast cancer.
The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic.
Hirsutine extracted from Uncaria rhynchophylla has been shown to exhibit anti-cancer activity. However, the molecular mechanism by which hirsutine exhibits anti-lung cancer activity remains unclear. In the present study, we showed that hirsutine induces apoptosis in human lung cancer cells via loss of mitochondrial membrane potential (∆ψm), adenosine triphosphate (ATP) depletion, ROS production, as well as cytochrome c release. Dephosphorylation of GSK3β is involved in hirsutine-mediated mitochondrial permeability transition pore (mPTP) opening through ANT1/CypD interaction. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K/Akt signaling pathway plays a critical role in hirsutine-mediated GSK3β dephosphorylation and mitochondrial apoptosis. Our in vivo study also showed that hirsutine effectively inhibits tumor growth in a A549 xenograft mouse model through ROCK1/PTEN/PI3K/Akt signaling-mediated GSK3β dephosphorylation and apoptosis. Collectively, these findings suggest a hierarchical model in which induction of apoptosis by hirsutine stems primarily from activation of ROCK1 and PTEN, inactivation of PI3K/Akt, leading in turn to GSK3β dephosphorylation and mPTP opening, and culminating in caspase-3 activation and apoptosis. These findings could provide a novel mechanistic basis for the application of hirsutine in the treatment of human lung cancer.
After having carefully checked the original data of Fig. 3, the authors noted that the student in their research group had inadvertently selected incorrect images for the 10 and 20 µM lycorine experiments to show the effect of lycorine on the migration of HepG2 cells during the figure compilation process. The corrected version of Fig. 3 is shown. The authors confirm that this error did not influence the statistical analysis shown for the migration of the cells, and neither were the overall results and conclusions of this article affected. The authors appreciate this opportunity to correct the scientific record, and all authors agree with this correction. Furthermore, the authors apologize for not noticing this error prior to publication, and for any inconvenience caused. [the original article was published in Oncology Reports 40: 2298‑2306, 2018; DOI: 10.3892/or.2018.6609]
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