No abstract

Glioblastoma is the most common and most aggressive primary brain malignancy. The multimodality treatments for this tumor including surgery, radiotherapy, and chemotherapy, are still not completely satisfied. Phenethyl isothiocyanate (PEITC), one member of the isothiocyanate family, has been shown to induce apoptosis in many human cancer cells. In this study, we investigate the pro-apoptotic effects caused by PETIC in human brain glioblastoma multiforme GBM 8401 cells. In our data, PEITC induced the cell morphological changes and decreased the cell viability of GBM8401 cells in a dose- and time-dependent manner. Moreover, the analysis of cell cycle distribution detected by flow cytometry showed that PEITC induced significantly sub-G1 phase (apoptotic population) in GBM 8401 cells. In addition, PEITC promoted the production of reactive oxygen species (ROS) and increase in [Ca2+]I, but decreased the mitochondrial membrane potential (ΔΨm) in treated cells. PEITC also induced caspases activities in GBM 8401 cells. Results from Western blot analysis indicated that PEITC promoted Fas, FasL, FADD, TRAIL, caspase-8, -9, -3, increased the pro-apoptotic protein (Bax, Bid and Bak), and inhibited the anti-apoptotic proteins (Bcl-2 and Bcl-xl) in GBM 8401 cells. Furthermore, PEITC promoted the release of cytochrome c, AIF and Endo G. GADD153, GRP 78, XBP-1 and IRE-1α, Calpain I and II in GBM 8401 cells. PEITC also promoted the expression of associated protein with endoplasmic reticulum (ER) stress. PEITC induces apoptosis through the extrinsic (death receptor) pathway, dysfunction of mitochondria, ROS induced ER stress, intrinsic (mitochondrial) pathway in GBM 8401 cells. The possible molecular mechanisms and signaling pathways of the anti-cancer properties of PEITC for human brain glioblastoma cells were postulated.

Forkhead box C1 (FOXC1) is a member of the forkhead family of transcription factors that are characterized by a DNA-binding forkhead domain. Increasing evidence indicates that FOXC1 is involved in tumor progression. However, the role of tumor hypoxia in FOXC1 regulation and its impact on lung cancer progression are unclear. Here, we report that FOXC1 was upregulated in hypoxic areas of lung cancer tissues from rodents or humans. Hypoxic stresses significantly induced FOXC1 expression. Moreover, hypoxia activated FOXC1 transcription via direct binding of hypoxia-inducible factor-1α (HIF-1α) to the hypoxia-responsive element (HRE) in the FOXC1 promoter. FOXC1 gain-of-function in lung cancer cells promoted cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition in vitro. However, a knockdown of FOXC1 in lung cancer cells inhibited these effects. Notably, knockdown of tumor hypoxia-induced FOXC1 expression via HIF-1-mediated FOXC1 shRNAs in lung cancer xenograft models suppressed tumor growth and angiogenesis. Finally, systemic delivery of FOXC1 siRNA encapsulated in lipid nanoparticles inhibited tumor growth and increased survival time in lung cancer-bearing mice. Taken together, these data indicate that FOXC1 is a novel hypoxia-induced transcription factor and plays a critical role in tumor microenvironment-promoted lung cancer progression. Systemic FOXC1 blockade therapy may be an effective therapeutic strategy for lung cancer.

Inflammatory processes have a detrimental role in the pathophysiology of ischemic stroke. However, little is known about the endogenous anti-inflammatory mechanisms in ischemic brain. Here, we identify CXCL14 as a critical mediator of these mechanisms. CXCL14 levels were upregulated in the ischemic brains of humans and rodents. Moreover, hypoxia inducible factor-1α (HIF-1α) drives hypoxia- or cerebral ischemia (CI)-dependent CXCL14 expression via directly binding to the CXCL14 promoter. Depletion of CXCL14 inhibited the accumulation of immature dendritic cells (iDC) or regulatory T cells (Treg) and increased the infarct volume, whereas the supplementation of CXCL14 had the opposite effects. CXCL14 promoted the adhesion, migration, and homing of circulating CD11c+ iDC to the ischemic tissue via the upregulation of the cellular prion protein (PrPC), PECAM-1, and MMPs. The accumulation of Treg in ischemic areas of the brain was mediated through a cooperative effect of CXCL14 and iDC-secreted IL-2-induced Treg differentiation. Interestingly, CXCL14 largely promoted IL-2-induced Treg differentiation. These findings indicate that CXCL14 is a critical immunomodulator involved in the stroke-induced inflammatory reaction. Passive CXCL14 supplementation provides a tractable path for clinical translation in the improvement of stroke-induced neuroinflammation.