scholarly journals Imperatorin induces autophagy and G0/G1 phase arrest via PTEN-PI3K-AKT-mTOR/p21 signaling pathway in human osteosarcoma cells in vitro and in vivo

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Minchao Lv ◽  
Qingxin Xu ◽  
Bei Zhang ◽  
Zhiqiang Yang ◽  
Jun Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Bioinformatic Analysis ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
Human Osteosarcoma Cells ◽  
G1 Phase Arrest

Abstract Background Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma still remains unsatisfactory in the past decades. Therefore, development of novel therapeutic agents which are effective to osteosarcoma and are safe to normal tissue simultaneously is quite essential and urgent. Methods Firstly, MTT assay, cell colony formation assay, cell migration and invasion assays were conducted to evaluate the inhibitory effects of imperatorin towards human osteosarcoma cells. RNA-sequence assay and bioinformatic analysis were then performed to filtrate and assume the potential imperatorin-induced cell death route and signaling pathway. Moreover, quantitative real-time PCR assay, western blot assay and rescue experiments were conducted to confirm the assumptions of bioinformatic analysis. Finally, a subcutaneous tumor-transplanted nude mouse model was established and applied to evaluate the internal effect of imperatorin on osteosarcoma by HE and immunohistochemistry staining. Results Imperatorin triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, imperatorin treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued imperatorin-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Conclusions This work firstly revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.

scholarly journals Peiminine Induces G0/G1-Phase Arrest, Apoptosis, and Autophagy via the ROS/JNK Signaling Pathway in Human Osteosarcoma Cells in Vitro and in Vivo

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Yu ◽  
Yuxi Chen ◽  
Shaohui Yuan ◽  
Yang Cao ◽  
Zhenggang Bi
Keyword(s):  
Signaling Pathway ◽  
Osteosarcoma Cells ◽  
Jnk Signaling ◽  
Human Osteosarcoma ◽  
Phase Arrest ◽  
Human Osteosarcoma Cells ◽  
G1 Phase Arrest ◽  
Jnk Signaling Pathway

Aims: Peiminine has been reported to have various pharmacological properties, including anticancer activity. In this study, we investigated the effect of this alkaloid on osteosarcoma and explored the underlying mechanisms.Methods: To evaluate the antiosteosarcoma effects of peiminine in vitro, cell viability was assessed by CCK-8 and live/dead assays; the effects of the drug on apoptosis and the cell cycle were examined by flow cytometry; the effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively, while its effects on autophagy were observed by transmission electron microscopy and an LC3 fluorescent puncta formation assay. The role of autophagy in the peiminine-mediated effects in osteosarcoma cells was evaluated by CCK-8 assay and western blotting after the application of the autophagy inhibitor chloroquine. The effect of peiminine on reactive oxygen species (ROS) production was analyzed using fluorescence confocal microscopy and spectrophotometry. Additionally, peiminine-treated osteosarcoma cells were exposed to SP600125, a JNK inhibitor, and N-acetylcysteine, a ROS scavenger, after which the contribution of the ROS/JNK signaling pathway to osteosarcoma was assessed using cell viability and LC3 fluorescent puncta formation assays, flow cytometry, and western blotting. A xenograft mouse model of osteosarcoma was generated to determine the antitumor effects of peiminine in vivo.Results: Peiminine suppressed proliferation and metastasis and induced cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells. These anticancer effects of peiminine were found to be dependent on intracellular ROS generation and activation of the JNK pathway. In line with these results, peiminine significantly inhibited xenograft tumor growth in vivo.Conclusions: Peiminine induced G0/G1-phase arrest, apoptosis, and autophagy in human osteosarcoma cells via the ROS/JNK signaling pathway both in vitro and in vivo. Our study may provide an experimental basis for the evaluation of peiminine as an alternative drug for the treatment of osteosarcoma.

Lycorine Induces Apoptosis and G1 Phase Arrest Through ROS/p38 MAPK Signaling Pathway in Human Osteosarcoma Cells In Vitro and In Vivo

Spine ◽  
2020 ◽  
Vol 45 (3) ◽  
pp. E126-E139 ◽  
Author(s):  
Lei Ning ◽  
Shuanglin Wan ◽  
Zhiwei Jie ◽  
Ziang Xie ◽  
Xiang Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mapk Signaling ◽  
G1 Phase ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Phase Arrest ◽  
Human Osteosarcoma Cells ◽  
G1 Phase Arrest

VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways

2020 ◽  
Vol 20 (8) ◽  
pp. 616-623 ◽  
Author(s):  
Jing-Yi Sun ◽  
Ya-Jun Hou ◽  
Hai-Juan Cui ◽  
Cheng Zhang ◽  
Ming-Feng Yang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Signaling Pathway ◽  
Tube Formation ◽  
G1 Phase ◽  
Mtor Signaling Pathway ◽  
Osteosarcoma Cells ◽  
Human Osteosarcoma ◽  
Phase Arrest ◽  
Human Osteosarcoma Cells ◽  
G1 Phase Arrest

Background: Activation of PI3K/mTOR signaling pathway plays key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of PI3K/mTOR pathway, and displayed potential anticancer activity. Objective: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells. Methods: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential. Results: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF. Conclusion: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

scholarly journals Diosmetin inhibits cell proliferation and promotes apoptosis through STAT3/c-Myc signaling pathway in human osteosarcoma cells

2021 ◽  
Vol 54 (1) ◽  
Author(s):  
Rende Ning ◽  
Guang Chen ◽  
Run Fang ◽  
Yanhui Zhang ◽  
Wenjuan Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Osteosarcoma Cells ◽  
Antitumor Property ◽  
Human Osteosarcoma ◽  
Cycle Arrest ◽  
Stat3 Phosphorylation ◽  
Human Osteosarcoma Cells ◽  
M Phase

Abstract Background Diosmetin is a bioflavonoid compound naturally abundant in citrus fruits. It is found to perform a variety of activities, while its antitumor property in osteosarcoma, a malignant tumor with unmet clinical treatment, remained unknown. Methods Colony formation assay, cell cycle analysis and apoptosis analysis were conducted respectively to observe the effect of diosmetin on cell proliferation and apoptosis in human osteosarcoma cells. Western blot and immunoprecipitation were used to detect the expression of apoptotic molecules and activation of STAT3/c-Myc pathway in Saos-2 and U2SO cells. Results Diosmetin significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and promoted cell apoptosis in both Saos-2 and U2SO cells. Moreover, Diosmetin downregulated the expression of anti-apoptotic protein Bcl-xL while upregulated the levels of pro-apoptotic proteins including cleaved Caspase-3, cleaved-PARP and Bax. Furthermore, diosmetin dose-dependently inhibited STAT3 phosphorylation, reduced the expression of its downstream protein c-Myc and impeded the interaction between STAT3 molecules. Conclusions These results suggest that diosmetin exerts anti-osteosarcoma effects by suppressing cell proliferation and inducing apoptosis via inhibiting the activation of STAT3/c-Myc signaling pathway, which provide the possibility for diosmetin to be a chemotherapeutic candidate for osteosarcoma.

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