Glioblastoma multiforme (GBM) presents a significant challenge in oncology due to its highly aggressive nature and inherent resistance to conventional therapeutic interventions. Vortioxetine, a novel antidepressant, exhibits anticancer abilities and can traverse the blood-brain barrier. In this study, the antitumor effect and mechanism of vortioxetine on GBM cells were investigated. Cell proliferation in GBM cells was assessed using the CCK8 and colony formation assays. Flow cytometry, western blot, and wound healing assay were used to study the mechanisms of vortioxetine. mCherry-GFP-LC3B and confocal microscopy were used to evaluate autophagic activity. RNA sequencing uses the capabilities of high-throughput sequencing methods to provide insight into the transcriptome of cells. Vortioxetine significantly inhibited the proliferation of GBM cells by inducing G1/G0 phase cell cycle arrest. Meanwhile, it also reduced the migratory capabilities of GBM cells. Furthermore, it promoted apoptotic cell death in GBM cells. In addition, it promoted autophagy in GBM cells, and autophagy inhibitors markedly enhanced its antiproliferative activities. Vortioxetine could down-regulate the expressions of PI3K and Akt, which were related to the occurrence and development of GBM. Our findings support the potential of vortioxetine as a novel therapeutic agent for GBM treatment. Vortioxetine exhibits anti-GBM activity via the PI3K-Akt signaling pathway. Meanwhile, our findings reveal autophagy inhibitors as an effective sensitizer for vortioxetine, offering new strategies for treating GBM.
2025. This work is openly licensed via CC BY 4.0.

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.
© 2024. The Author(s).

Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)‑1α in liver cancer cells. However, to date, no selective HIF‑1α inhibitor has been clinically approved. The aim of this study is to investigate a drug‑targetable molecule that can regulate HIF‑1α under hypoxia. The present study demonstrated that hyperactivation of dual‑specificity tyrosine‑phosphorylation‑regulated kinase 1A (DYRK1A)/HIF‑1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF‑1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpression‑vector transfection in liver cancer cell lines notably induced HIF‑1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF‑1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF‑1α and positively regulate HIF‑1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the anti‑liver cancer effects of regorafenib and sorafenib under hypoxia. Co‑treatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF‑1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF‑1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.

The overall outcomes for patients with advanced liver cancer are far from satisfactory, and the development of more effective therapeutic strategies for liver cancer is required. Sulforhodamine blue and colony formation assays were performed to detect the proliferation of liver certain cancer cells, including HepG2 and Hep3B. Western blotting was also preformed to detect the expression of indicated proteins, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase, dual-specificity tyrosine phosphorylation kinase 1A (DYRK1A), PARP-1/2, GAPDH, myeloid cell leukemia-1, phosphorylated-AKT (Ser473), caspase-3, α-tubulin and AKT. PI staining was used to detect cell death. In the present study, DYRK1A knockdown significantly enhanced the anti-liver cancer effect of regorafenib in vitro. Furthermore, DYRK1A inhibitor harmine together with regorafenib provided synergistic anti-liver cancer activity by suppressing cell proliferation. In addition, harmine significantly enhanced regorafenib-induced cell death in liver cancer cells. It has been reported that AKT signaling is activated in regorafenib-resistant cancer cells and plays a crucial role in the regulation of cellular sensitivity to regorafenib. In the present study, AKT was activated in regorafenib-treated cells, and harmine could suppress the activation of AKT and reinforce the anti-cancer effects of regorafenib via regulating AKT in liver cancer cells. These data indicated that harmine enhanced the anti-cancer effects of regorafenib on suppressing cell proliferation and inducing apoptosis in liver cancer cells via regulating the activation of AKT, and harmine plus regorafenib may be a potential therapeutic regimen for treating patients with liver cancer.
Copyright: © Chen et al.

Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes the beta-subunit of N-acetyl-beta-hexosaminidase A and B, resulting in the accumulation of the ganglioside GM2. We isolated astrocytes from the neonatal brain of Sandhoff disease model mice in which the N-acetyl-beta-hexosaminidase beta-subunit gene is genetically disrupted (ASD). Glycolipid profiles revealed that GM2/GA2 accumulated in the lysosomes and not on the cell surface of ASD astrocytes. In addition, GM3 was increased on the cell surface. We found remarkable differences in the cell proliferation of ASD astrocytes when compared with cells isolated from wild-type mice, with a faster growth rate of ASD cells. In addition, we observed increased extracellular, signal-regulated kinase (ERK) phosphorylation in ASD cells, but Akt phosphorylation was decreased. Furthermore, the phosphorylation of ERK in ASD cells was not dependent upon extracellular growth factors. Treatment of ASD astrocytes with recombinant N-acetyl-beta-hexosaminidase A resulted in a decrease of their growth rate and ERK phosphorylation. These results indicated that the up-regulation of ERK phosphorylation and the increase in proliferation of ASD astrocytes were dependent upon GM2/GA2 accumulation. These findings may represent a mechanism in linking the nerve cell death and reactive gliosis observed in Sandhoff disease.