Cucurbitacin-B Exerts Anticancer Effects through Instigation of Apoptosis and Cell Cycle Arrest within Human Prostate Cancer PC3 Cells via Downregulating JAK/STAT Signaling Cascade

Alafnan, Ahmed; Alamri, Abdulwahab; Hussain, Talib; Rizvi, Syed Mohd Danish

doi:10.3390/ph15101229

Cited by 10 publications

(7 citation statements)

References 38 publications

(62 reference statements)

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“…By analysing and calculating the significance level of protein enrichment of each pathway, we found that the differential protein was enriched in JAK-STAT and mTOR signalling pathways ( Figure 5(e) ). And these signal pathways were closely related to cell cycle regulation and ROS metabolism in previous studies [ 22 – 25 ]. These results suggested that the knockdown of p16 INK4a may promote CM proliferation by regulating cell cycle progression and ROS metabolism.…”

Section: Resultsmentioning

confidence: 86%

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

Sun

Zhou

Yang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Neonatal mice achieve complete cardiac repair through endogenous myocardial regeneration after apical resection (AR), but this capacity is rapidly lost 7 days after birth. As an upstream inhibitor of cyclin-dependent kinase 4/6- (CDK4/6-) mediated cell cycle activity, p16INK4a is widely involved in regulating tumor and senescence. Given that p16INK4a had a significant negative regulation on cell proliferation, targeting cardiomyocytes (CMs) to inhibit p16INK4a seems to be a promising attempt at myocardial regeneration therapy. The p16INK4a expression was upregulated during perimyocardial regeneration time. Knockdown of p16INK4a stimulated CM proliferation, while p16INK4a overexpression had the opposite effect. In addition, p16INK4a knockdown prolonged the proliferation time window of newborn myocardium. And p16INK4a overexpression inhibited cell cycle activity and deteriorated myocardial regeneration after AR. The quantitative proteomic analysis showed that p16INK4a knockdown mediated the cell cycle progression and intervened in energy metabolism homeostasis. Mechanistically, overexpression of p16INK4a causes abnormal accumulation of reactive oxygen species (ROS) to induce autophagy, while scavenging ROS with N-acetylcysteine can alleviate autophagy and regulate p16INK4a, CDK4/6, and CyclinD1 in a covering manner. And the effect of inhibiting the proliferation of p16INK4a-activated CMs was significantly blocked by the CDK4/6 inhibitor Palbociclib. In summary, p16INK4a regulated CM proliferation progression through CDK4/6 and ROS-related autophagy to jointly affect myocardial regeneration repair. Our study revealed that p16INK4a might be a potential therapeutic target for myocardial regeneration after injury.

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Section: Resultsmentioning

confidence: 86%

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

Sun

Zhou

Yang

et al. 2023

Oxidative Medicine and Cellular Longevity

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“…Notably, some genes were present in multiple pathways, indicating a shared involvement. Whilst the involvement of the JAK/STAT pathway has been highlighted in previous research (Zhang et al, 2022), and the inhibitory role of CuB on STAT has been documented in various studies (Alafnan et al, 2022;Wang et al, 2021;Yar Saglam et al, 2016)…”

Section: Discussionmentioning

confidence: 97%

“…Specifically, in cancers including lung (Liu, Li, et al, 2022;Shang et al, 2023), colorectal (Huang et al, 2023;Zhang et al, 2022) and hepatocellular carcinomas (Chan et al, 2010;Ge et al, 2018), CuB has shown the potential to inhibit tumour cell activities through diverse mechanisms, including signalling pathway inhibition (Liu, Li, et al, 2022) and cell cycle arrest (Chan et al, 2010). Additionally, CuB's effects have been noted in other cancers, including breast cancer, prostate cancer and osteosarcoma, amongst others (Alafnan et al, 2022(Alafnan et al, , 2023Garg et al, 2020;Jin et al, 2018;Liang et al, 2019;Zhang et al, 2017). Several studies have highlighted the suppressive effects of CuB on the STAT signalling pathway in various cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, CuB counteracts the tumourigenic effects of CD133+ HepG2 liver cancer stem cells by inhibiting the JAK2/STAT3 pathway (Wang et al, 2021). In prostate cancer PC3 cells, CuB triggers apoptosis and cell cycle arrest by downregulating the JAK/STAT pathway (Alafnan et al, 2022). Zhang et al revealed that CuB induced apoptosis in colorectal cancer cells and reduced M2 macrophage polarisation via the JAK2/STAT3 pathway (Zhang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Cucurbitacin B modulates M2 macrophage differentiation and attenuates osteosarcoma progression via PI3K/AKT pathway

Wu,

Ma,

et al. 2024

Phytotherapy Research

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Osteosarcoma is a common malignant bone tumour characterised by an aggressive metastatic potential. The tumour microenvironment, particularly the M2‐polarised macrophages, is crucial for tumour progression. Cucurbitacin B (CuB), a triterpenoid derivative, is recognised for its anti‐inflammatory and antitumour properties. This study investigates CuB and its effect on M2 macrophage differentiation and osteosarcoma progression, aiming to contribute to new treatment strategies. In vitro, THP‐1 monocytes were stimulated with PMA, IL‐13 and IL‐4 to induce differentiation into M2 macrophages. Additionally, the influence of CuB on the proliferation, migration and invasion of osteosarcoma cells in the context of M2 macrophages was scrutinised. Crucial signalling pathways, especially the PI3K/AKT pathway, affected by CuB were identified and validated. In vivo, the osteosarcoma model was employed to gauge the effects of CuB on tumour weight, lung metastasis, angiogenesis, cell proliferation and M2 macrophage markers. The results showed that CuB inhibited M2 macrophage differentiation, leading to reduced proliferation, migration and invasion of osteosarcoma cells. CuB manifested an inhibitory effect on the PI3K/AKT pathway during the differentiation of M2 macrophages. In mouse models, CuB markedly reduced the tumour weight and the number of lung metastases. It also reduced the expression of angiogenesis and cell proliferation markers in tumour tissues, decreased the quantity of M2 macrophages and their associated markers and pathway proteins. In conclusion, CuB impedes osteosarcoma progression by inhibiting M2 macrophage differentiation via the PI3K/AKT pathway, presenting the potential for therapeutic advancements in osteosarcoma treatment.

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“…Mitochondrial viability in A549 cells was further assessed through Rhodamine (Rh)-123 staining per the protocol described previously [ 49 ]. Briefly, 1 × 10 4 A549 cells were exposed to stated concentrations of GAN and MTX either alone or in combination for 12 h. Subsequently, the cells were re-exposed to the Rh-123 stain (5 mg/mL) and incubated in the dark at room temperature for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells

et al. 2023

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Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.

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Cucurbitacin-B Exerts Anticancer Effects through Instigation of Apoptosis and Cell Cycle Arrest within Human Prostate Cancer PC3 Cells via Downregulating JAK/STAT Signaling Cascade

Cited by 10 publications

References 38 publications

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

P16INK4a Regulates ROS-Related Autophagy and CDK4/6-Mediated Proliferation: A New Target of Myocardial Regeneration Therapy

Cucurbitacin B modulates M2 macrophage differentiation and attenuates osteosarcoma progression via PI3K/AKT pathway

Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells

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