scholarly journals Micheliolide Enhances Radiosensitivities of p53-Deficient Non-Small-Cell Lung Cancer via Promoting HIF-1α Degradation

2020 ◽  
Vol 21 (9) ◽  
pp. 3392
Author(s):  
Peizhong Kong ◽  
K.N. Yu ◽  
Miaomiao Yang ◽  
Waleed Abdelbagi Almahi ◽  
Lili Nie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Hypoxic Exposure ◽  
Dependent Manner ◽  
Wild Type ◽  
Small Cell Lung ◽  
H460 Cells ◽  
Wild Type P53

Micheliolide (MCL) has shown promising anti-inflammatory and anti-tumor efficacy. However, whether and how MCL enhances the sensitivity of non-small-cell lung cancer (NSCLC) to radiotherapy are still unknown. In the present paper, we found that MCL exerted a tumor cell killing effect on NSCLC cells in a dose-dependent manner, and MCL strongly sensitized p53-deficient NSCLC cells, but not the cells with wild-type p53 to irradiation (IR). Meanwhile, MCL markedly inhibited the expression of hypoxia-inducible factor-1α (HIF-1α) after IR and hypoxic exposure in H1299 and Calu-1 cells rather than in H460 cells. Consistently, radiation- or hypoxia-induced expression of vascular endothelial growth factor (VEGF) was also significantly inhibited by MCL in H1299 and Calu-1 cells, but not in H460 cells. Therefore, inhibition of the HIF-1α pathway might, at least in part, contribute to the radiosensitizing effect of MCL. Further study showed that MCL could accelerate the degradation of HIF-1α through the ubiquitin-proteosome system. In addition, the transfection of wild-type p53 into p53-null cells (H1299) attenuated the effect of MCL on inhibiting HIF-1α expression. These results suggest MCL effectively sensitizes p53-deficient NSCLC cells to IR in a manner of inhibiting the HIF-1α pathway via promoting HIF-1α degradation, and p53 played a negative role in MCL-induced HIF-1α degradation.

Wild-Type p53 Overexpression and Its Correlation With MDM2 and p14ARF Alterations: An Alternative Pathway to Non–Small-Cell Lung Cancer

2005 ◽  
Vol 23 (1) ◽  
pp. 154-164 ◽  
Author(s):  
Yu-Chien Wang ◽  
Ruo-Kai Lin ◽  
Yi-Hung Tan ◽  
Jung-Ta Chen ◽  
Chih-Yi Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
P53 Protein ◽  
Small Cell ◽  
Sequencing Analysis ◽  
Nuclear Staining ◽  
Wild Type ◽  
Small Cell Lung ◽  
Wild Type P53

Purpose We found a relatively reduced frequency of p53 mutation with a much greater frequency of p53 protein overexpression, which reflected stabilization of p53 protein in the absence of p53 gene mutation. Therefore, we investigated the possibility of alternative mechanisms leading to p53 protein stabilization. Patients and Methods We performed gene and protein alteration studies on p53 and its upstream effectors, MDM2 and p14ARF, in tumors from 94 non–small-cell lung cancer (NSCLC) patients. Results Immunohistochemical and sequencing analyses indicated that 37 tumors showed overexpression of wild-type p53. An absence of nuclear staining of MDM2 protein was found in 95% of these tumors (35 of 37; P < .001). The tumors with negative MDM2 staining showed a significantly high concordance of loss of Akt activity and low MDM2 mRNA expression (P < .001). Sequencing analysis revealed five distinct MDM2 splicing variants disrupting the conserved p53 binding domain. Corresponding variant proteins were detected in three lung cancer cell lines using the Western blot analysis. Our results also indicated that among the tumors with overexpression of the wild-type p53, 92% (34 of 37) showed immunoreactivity to p14ARF (P = .001). In addition, the deregulation of p53 and MDM2 genes was significantly associated with squamous lung cancer (P < .05) and was correlated with advanced stages (P < .05) and poor prognosis (P < .05). Conclusion Our data suggest that immunopositivity of p14ARF together with a low expression of MDM2 contributes to accumulation of the wild-type p53, and that deregulation of the p53-MDM2-p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC.

scholarly journals FNC Inhibits Proliferation and Metastasis of Non-Small-Cell Lung Cancer in Vivo and In Vitro

2021 ◽  
Author(s):  
Xiang Jing ◽  
Shuai Niu ◽  
Yi Liang ◽  
Huiping Chen ◽  
Ning Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
H460 Cells ◽  
Proliferation And Metastasis

Abstract Background: Non-small-cell lung cancer (NSCLC) is associated with the highest morbidity and mortality rate, and chemotherapy is the primary therapy for NSCLC. However, the clinical outcome is still far from satisfactory. This study aimed to determine the effects and mechanisms of FNC on NSCLC. Results: FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, is a novel cytidine analogue, inhibits the proliferation and metastasis of H460 cells in a time- and dose-dependent manner in vitro. Mechanistically, treatment of H460 cells with FNC inhibits Bcl-2 expression and potentiates Cytochrome C (Cyt-C) release, Bax and caspase-3 expression. In parallel, FNC inhibits tumor migration, invasion and metastasis in H460 cells by increasing E-cadherin protein levels and reducing the expression of VEGF, MMP-2, MMP-9 proteins. And murine models and mouse xenograft models also proved that FNC could significantly inhibit NSCLC tumor growth and metastasis with low toxicity. Finally, we also discovered that inhibition of DNMT3B expression is one of the important mechanisms of FNC inhibiting proliferation and metastasis of NSCLC cells. Conclusions: FNC induces apoptosis through the mitochondrial apoptotic pathway and represses tumor progression by targeting multiple proteins related to cell adhesion and invasion in vitro and in vivo. Meanwhile, FNC was involved in regulating DNA methylation. In summary, our results support the further development of FNC as potential therapeutics for clinical non-small cell lung cancer.

GPRC5a suppresses the proliferation of non-small cell lung cancer under wild type p53 background

2020 ◽  
Vol 46 (7) ◽  
pp. 226-233
Author(s):  
Jin Er ◽  
Li Chao ◽  
Li Yiwei ◽  
Xing Feng ◽  
Zhao Fei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Wild Type P53

scholarly journals Bufalin down-regulates Axl expression to inhibit cell proliferation and induce apoptosis in non-small-cell lung cancer cells

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Nam-Yi Kim ◽  
Young-Ah Suh ◽  
Soyoung Kim ◽  
ChuHee Lee
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Protein Level ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
H460 Cells

Abstract Axl, a member of the TAM (Tyro3, AXL, Mer) receptor tyrosine kinase family, plays critical roles in cell growth, proliferation, apoptosis, and migration. In the present study, we demonstrated that the anti-cancer activity of bufalin, a major bioactive component of the Chinese traditional medicine Chan Su, is mediated by the down-regulation of Axl in non-small-cell lung cancer (NSCLC) cells. We observed the inhibitory effect of bufalin on the proliferation of A549 and H460 NSCLC cells and the clonogenicity of these cells was reduced by bufalin treatment in a dose-dependent manner. Next, we found that the protein level of Axl was decreased in proportion to the concentration of bufalin in both A549 and H460 cells. Moreover, the promoter activity of the Axl gene was decreased by bufalin in a dose- and time-dependent manner, indicating that bufalin down-regulates Axl gene expression at the transcriptional level. We further examined if the anti-proliferative property of bufalin is influenced by Axl at the protein level. Axl overexpression attenuated the effect of bufalin in inhibiting cell proliferation and colony formation and inducing apoptosis in H460 cells, while knockdown of Axl gene expression induced the opposite effect. Taken together, our data indicate that the anti-proliferative and pro-apoptotic effects of bufalin were associated with the protein level of Axl, suggesting that Axl is a potent therapeutic target of bufalin in suppressing proliferation and inducing apoptosis in NSCLC cells.

scholarly journals Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells

2000 ◽  
Vol 7 (4) ◽  
pp. 537-544 ◽  
Author(s):  
Yoshitsugu Horio ◽  
Yoshinori Hasegawa ◽  
Yoshitaka Sekido ◽  
Masahide Takahashi ◽  
Jack A Roth ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Synergistic Effects ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Wild Type ◽  
Small Cell Lung ◽  
Wild Type P53

A Case of EGFR-wild-type Adenocarcinoma of Recurrent Non-small Cell Lung Cancer Responding to Erlotinib

Haigan ◽  
2012 ◽  
Vol 52 (3) ◽  
pp. 315-319
Author(s):  
Masami Morimoto ◽  
Naoki Hino ◽  
Hisashi Matsuoka ◽  
Takanori Miyoshi ◽  
Masaru Tsuyuguchi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung
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