Cistanche phenylethanoid glycosides induce apoptosis and pyroptosis in T-cell lymphoma.

Cistanche deserticola, known for its extensive history in Traditional Chinese Medicine (TCM), is valued for its therapeutic properties. Recent studies have identified its anticancer capabilities, yet the mechanisms underlying these properties remain to be fully elucidated. In this study, we determined that a mixture of four cistanche-derived phenylethanoid glycosides (CPhGs), echinacoside, acteoside, 2-acetylacteoside, and cistanoside A, which are among the main bioactive compounds in C. deserticola, eliminated T-cell lymphoma (TCL) cells by inducing apoptosis and pyroptosis in vitro and attenuated tumor growth in vivo in a xenograft mouse model. At the molecular level, these CPhGs elevated P53 by inhibiting the SIRT2-MDM2/P300 and PI3K/AKT carcinogenic axes and activating PTEN-Bax tumor-suppressing signaling. Moreover, CPhGs activated noncanonical and alternative pathways to trigger pyroptosis. Interestingly, CPhGs did not activate canonical NLRP3-caspase-1 pyroptotic signaling pathway; instead, CPhGs suppressed the inflammasome factor NLRP3 and the maturation of IL-1ß. Treatment with a caspase-1/4 inhibitor and silencing of Gasdermin D (GSDMD) or Gasdermin E (GSDME) partially rescued CPhG-induced cell death. Conversely, forced expression of NLRP3 restored cell proliferation. In summary, our results indicate that CPhGs modulate multiple signaling pathways to achieve their anticancer properties and perform dual roles in pyroptosis and NLRP3-driven proliferation. This study offers experimental support for the potential application of CPhGs in the treatment of TCL.

[miR-181c promotes the migration and angiogenesis of human A549 cells via targeting inhibition of reversion-inducing cysteine-rich protein with Kazal motifs (RECK)].

Objective To investigate the impact of miR-181c on migration and angiogenesis of lung cancer cells. Methods The Oncomine platform, UALCAN was used to analyze the differential expression of miR-181c and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in lung cancer obtained from the Cancer Genome Atlas (TCGA) database. The targeting relationship between miR-181c on RECK gene was predicted using Targetscan software. miR-181c mimic, inhibitor and negative control were introduced into A549 cells respectively. After transfection, the real-time quantitative PCR was used to detect the relative expressions of miR-181c and RECK mRNA, and Western blot analysis was used to detect the expression levels of RECK, matrix metalloproteinase 2 (MMP2) and MMP9 proteins. TranswellTM assay was performed to analyze the cell migration ability. The secretion of vascular endothelial growth factor (VEGF)-A in the cell culture supernatant was analyzed by using ELISA. Human umbilical vein endothelial cells (HUVECs) were treated with the culture supernatant, then in vitro tubule formation assay was carried out to evaluate the angiogenesis ability. The targeting correlation between miR-181c and RECK was validated by double luciferase reporter gene assay. Results UALCAN analysis displayed that the expression of miR-181c was significantly higher and RECK expression was significantly lower in lung cancer tissues compared to that in normal tissues. Targetscan prediction showed that there was a miR-181c binding site in the 3'-untranslated region (3' UTR) of RECK gene. miR-181c could downregulate the expression of RECK, increase the expressions of MMP2 and MMP9, and promote the A549 cell migration. ELISA and tubule formation assay showed that miR-181c could induce the secretion of VEGF-A in A549 cells and enhance the ability of HUVECs differentiae into tubules. The double luciferase reporter gene assay confirmed that RECK was the direct regulation target of miR-181c. Conclusion miR-181c promotes the migration and angiogenesis of human A549 cells by directly targeting RECK.

Gentian violet induces apoptosis and ferroptosis via modulating p53 and MDM2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancies with limited curative options and poor prognosis. Gentian violet (GV) has recently been found to have anti-tumor properties with promising clinical applications. However, its anti-tumor effect and the underlying functional mechanisms in HCC have not been investigated. In this study, we found that GV induced ferroptosis and apoptosis, inhibited cell proliferation, migration and invasion in a dose-dependent manner in vitro, and significantly attenuated the growth of HCC in vivo. Both ferroptosis inhibitor Ferrostain-1 (Fer-1) and apoptosis inhibitor Z-VAD-KFM (Z-VAD) partially attenuated GV-induced growth-inhibitory effects, while combined treatment of Fer-1 and Z-VAD completely abolished GV's activities. Increased levels of intracellular reactive oxygen species (ROS) were detected after GV treatment. Interestingly, GV elevated the expression levels of both p53 and its negative regulator MDM2, which was dependent on the expression of the dehydrogenase/reductase protein Hep27. Simultaneously silencing both the MDM2 and p53 genes by siRNAs abolished ROS production and partially rescued the cell death induced by GV treatment. Our data demonstrate a GV-Hep27-MDM2-p53 signaling cascade that regulates ferroptosis and apoptosis. Furthermore, our findings provide insights into understanding the anti-tumor function of GV and present the basis of new therapeutic strategies for the treatment of HCC.