Effects of aspirin on proliferation, invasion and apoptosis of Hep‑2 cells via the PTEN/AKT/NF‑κB/survivin signaling pathway

Jin, Mingji; Li, Chunyu; Zhang, Qiang; Xing, Shu; Kan, Xuan; Wang, Jiayu

doi:10.3892/ol.2018.8377

Cited by 14 publications

(10 citation statements)

References 21 publications

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“…The reduction in quantity of CD19.CAR-T cells displaying significant decreases of both CD4 + and CD8 + CD19.CAR-T cells should be taken into account to this negative effect of NSAIDs on CD19.CAR-T cells. This is might be a consequence of the down-regulation of antiapoptotic Bcl-2 family members like Bcl-xl in CD19.CAR-T cells, thereby triggering the intrinsic mitochondrial apoptosis pathway in order to induce cell death by apoptosis, which is confirmed by our data and previous studies (17,(19)(20)(21)(22)(23).…”

Section: Discussionsupporting

confidence: 89%

Dual Effects of Cyclooxygenase Inhibitors in Combination With CD19.CAR-T Cell Immunotherapy

Yang

Wang

et al. 2021

Front. Immunol.

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Chimeric antigen receptor T (CAR-T) cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include nonsteroidal anti-inflammatory drugs (NSAIDs) like cyclooxygenase (COX) inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10 red to JC-10 green CAR-T cells from 6.46 ± 7.03 (mean ± SD) to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10 red to JC-10 green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation of expression of CD27 on CD4+ and CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+ and CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.

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Section: Discussionsupporting

confidence: 89%

Dual Effects of Cyclooxygenase Inhibitors in Combination With CD19.CAR-T Cell Immunotherapy

Yang

Wang

et al. 2021

Front. Immunol.

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“…Aspirin has a profound apoptotic effect on cancer cells via Akt, β-catenin, NF-κB or ER stress. The diverse signals converge at the mitochondria where they are integrated, resulting in anti-apoptotic protein downregulation and/or pro-apoptotic protein upregulation [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Mitochondria are central to the coordination of anti-apoptotic and pro-apoptotic networks, and are strictly controlled by Bax- or Bak-based pore channels.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

Chang

Pan

et al. 2020

IJMS

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Clinically, high cyclooxygenase-2 expression in malignant glioma correlates well with poor prognosis and the use of aspirin is associated with a reduced risk of glioma. To extend the current understanding of the apoptotic potential of aspirin in most cell types, this study provides evidence showing that aspirin induced glioma cell apoptosis and inhibited tumor growth, in vitro and in vivo. We found that the human H4 glioma cell-killing effects of aspirin involved mitochondria-mediated apoptosis accompanied by endoplasmic reticulum (ER) stress, Noxa upregulation, Mcl-1 downregulation, Bax mitochondrial distribution and oligomerization, and caspase 3/caspase 8/caspase 9 activation. Genetic silencing of Noxa or Bax attenuated aspirin-induced viability loss and apoptosis, while silencing Mcl-1 augmented the effects of aspirin. Data from genetic and pharmacological studies revealed that the axis of ER stress comprised an apoptotic cascade leading to Noxa upregulation and apoptosis. The apoptotic programs and mediators triggered by aspirin in H4 cells were duplicated in human U87 glioma cell line as well as in tumor-bearing BALB/c nude mice. The involvement of ER stress in indomethacin-induced Mcl-1 downregulation was reported in our previous study on glioma cells. Therefore, the aforementioned phenomena indicate that ER stress may be a valuable target for intervention in glioma apoptosis.

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“…Wu et al ( 41 ), found that PTEN overexpression suppressed the growth of bladder cancer cells and significantly induced apoptosis via the downregulation of Survivin and caspase cascade activation. As previously demonstrated, following treatment with aspirin, Hep-2 cells exhibited a significant upregulation of PTEN and the inhibition of nuclear factor (NF)-κB and Survivin, the downstream targets of the PTEN/protein kinase B (AKT) signaling pathway, suggesting that the anticancer molecular mechanism of aspirin may be associated with the inhibition of tumor invasion and the induction of apoptosis by regulating the activity of the PTEN/AKT/NF-κB/Survivin signaling pathway ( 42 ). The aforementioned findings suggest that there may be an association between Survivin and PTEN.…”

Section: Discussionmentioning

confidence: 99%

Expression and clinical correlation of Survivin and PTEN in gastric cancer patients

et al. 2020

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Reports on the correlation between the expression of Survivin/phosphatase and tensin homolog (PTEN) proteins and clinical factors in gastric cancer (GC) are varied, and the sample sizes were also not sufficient. The present study aimed to detect the expression of Survivin and PTEN proteins in GC patients on the basis of a greater number of specimens and to analyze the correlation with clinical features and survival. The results revealed that the Survivin expression rates in GC, normal tissues and metastatic lymph nodes were 72% (232/322), 5% (6/120) and 80% (36/45), respectively, while the PTEN expression rates were 34% (109/322), 92.5% (111/120) and 24.4% (11/45), respectively, and the differences between cancer and normal tissue or metastatic lymph nodes were significant for both proteins (P<0.05). The expression of Survivin was significantly associated with gross type, depth of invasion, distant metastasis, tumor, necrosis and metastasis (TNM) stage and vascular invasion, while PTEN expression was predominantly associated with age, tumor size, invasion depth, TNM stage and lymphatic invasion in GC patients (P<0.05). The expression of both was associated with postoperative metastasis and metastatic site (P= 0.007 and P= 0.011 for Survivin, and P= 0.002 and P= 0.005 for PTEN). There was a negative association between the expression levels of Survivin and PTEN (P= 0.001, r=-0.524). The expression levels of both were also associated with prognosis. The expression of Survivin and PTEN protein exhibit opposing trends in GC, which may indicate adverse biological effects in the occurrence of GC. The Survivin and PTEN expression levels are likely to be an important molecular event in gastric tumorigenesis and may be considered as molecular markers of GC progression and reliable prognostic indicators of GC.

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Effects of aspirin on proliferation, invasion and apoptosis of Hep‑2 cells via the PTEN/AKT/NF‑κB/survivin signaling pathway

Cited by 14 publications

References 21 publications

Dual Effects of Cyclooxygenase Inhibitors in Combination With CD19.CAR-T Cell Immunotherapy

Dual Effects of Cyclooxygenase Inhibitors in Combination With CD19.CAR-T Cell Immunotherapy

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

Expression and clinical correlation of Survivin and PTEN in gastric cancer patients

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