CSTP1 inhibits IL-6 expression through targeting Akt/FoxO3a signaling pathway in bladder cancer cells

Zhuo, Dexiang; Wu, Yongyang; Luo, Jia; Deng, Ling; Niu, Xiaohua

doi:10.1016/j.yexcr.2019.04.019

Cited by 13 publications

(16 citation statements)

References 40 publications

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“…Generally, IL-6 is known to modulate the self-renewal of stem cells by phosphorylating the STAT3, MAPK and Akt signaling pathways. [51][52][53][54] Other research has shown that both constitutive and IL-6-inducible activation of STAT3 (Tyr705) and JAK2 can occur in osteosarcoma. 55 In agreement with the opinion of Peng et al, 27 Figure 7 shows that the overexpression of STAT3 offset the cinobufagin-induced reduction in CD133-positive cell ratios and the dimension of spheroids as well as the cinobufagin-induced increase in the expression of Bax, caspase-3, cleaved PARP, vimentin and α-SMA, and the lower levels of Bcl-2 and E-cad.…”

Section: Discussionmentioning

confidence: 99%

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Zhang¹,

Ma²,

Li³

2019

DDDT

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Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/a2KF0PMRBDo Background: Current clinical treatments for osteosarcoma are limited by disease recurrence and primary or secondary chemoresistance. Cancer stem-like cells have been proposed to facilitate the initiation, progression, recurrence and chemoresistance of osteosarcoma. Furthermore, previous studies have reported that IL-6-STAT3 pathway is overexpressed in various types of cancer and contributes to cell proliferation, apoptosis, invasion/migration, chemoresistance and modulation of stemness features. Aim: To examined the effect of cinobufagin on cancer progression and modulation of stemness features in osteosarcoma, and investigated the molecular mechanisms underlying such effects. Methods: Human osteosarcoma cell lines U2OS/MG-63 were recruited in this study. Cell proliferation, migration, and invasion were determined by MTT assay, colony formation assay,wound healing assay, and cell invasion assay respectively. Its effect on stemness was assessed by flow cytometry and mammosphere formation. The protein expression levels of related proteins were detected by Western blot. The xenograft model, immunofluorescence staining and immunohistochemistry were used to determine the effect of cinobufagin on tumorigenicity in vivo experiment. Results: We found that cinobufagin suppressed the viability of U2OS/MG-63 spheroids/ parent cells in a time-and dose-dependent manner. Notably, cinobufagin had no effect on the viability of hFOB 1.19 cells. Moreover, cinobufagin induced apoptosis, increased the width of wounds, reduced invasive osteosarcoma spheroids/parent cell numbers and reduced EMT phenotype and OPN levels in U2OS/MG-63 spheroids as well as U2OS/MG-63 parent cells lines. Noticeablely, we found that OPN levels were higher in spheroids group than that in parent cells. In addition, cinobufagin ameliorated the proportion of CD133-positive cells, the size of spheroids and Nanog, Sox-2 and Oct3/4 protein levels. Our in vivo experiments showed that cinobufagin consistently reduced tumor volume,the expressions of OPN, Sox-2, Oct3/4, Nanog and p-STAT3 by the immuno histochemistry staining as well as CD133 expression in tumor tissues by immunofluorescence analysis. From a mechanistic point of view, cinobufagin was shown to inhibit IL-6-OPN-STAT3 signaling pathway. Exogenous IL-6/OE-OPN/overexpression STAT3 attenuated the induction of cinobufagin-mediated apoptosis and the suppression of stemness properties respectively. Conclusion: Collectively, our data demonstrated that cinobufagin inhibited the viability and tumorigenesis capability of osteosarcoma cells by blocking IL-6-OPN-STAT3 signaling pathway. Cinobufagin may therefore represent a promising therapeutic agent for osteosarcoma management.

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Section: Discussionmentioning

confidence: 99%

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Zhang¹,

Ma²,

Li³

2019

DDDT

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“…7 As a multifunctional cytokine, IL-6 is involved in the progression of bladder cancer. 11,12 As shown in Figure 4A, desloratadine treatment significantly reduced the IL-6 level in EJ cells (P < .05). Moreover, upregulation of IL-6 could partially restore the inhibitory effect of desloratadine on EJ cell invasion compared with desloratadinetreated cells ( Figure 4B).…”

Section: Upregulation Of Il-6 Partially Restored the Anticancer Activmentioning

confidence: 83%

Desloratadine, a Novel Antigrowth Reagent for Bladder Cancer

et al. 2020

Technol Cancer Res Treat

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Desloratadine, a potent antagonist for human histamine H1 receptor, has been revealed to exhibit antihistaminic activity and anti-inflammatory activity. However, it is not yet known whether desloratadine has any effect on the biological behaviors of tumor cells. In this study, we aimed to investigate the effects of desloratadine on cell growth and invasion in bladder cancer EJ and SW780 cells in vitro. We observed that desloratadine inhibited cell viability of EJ and SW780 cells in a dose- and time-dependent manner. Desloratadine treatment was also revealed to suppress colony-formation ability and induce cell cycle arrest at G1 phase in EJ cells. Desloratadine promoted cell apoptosis via modulating the expression of Bcl-2, Bax, cleaved caspase 3, and cleaved caspase 9 in EJ and SW780 cells. Western blot resulted showed that desloratadine also impaired the expression of autophagy-related proteins, such as Beclin 1, P62, and LC3I/II in EJ and SW780 cells; while autophagy inhibitor LY294002 reversed the effects of desloratadine on these proteins. Moreover, desloratadine remarkably attenuated cell migration and invasion. Furthermore, we illustrated that desloratadine downregulated the expression of N-cadherin, Vimentin, Snail1, and Snail2, while upregulated the expression of E-cadherin in EJ and SW780 cells in vitro. The level of interleukin 6 was reduced in desloratadine-treated cells, while upregulation of interleukin 6 significantly abolished the anticancer activity of desloratadine in cell invasion and Bcl-2, Bax, Beclin1, LC3-I/II, N-cadherin, and E-cadherin expression in EJ cells. Taken together, our data suggest a potential anticancer activity of desloratadine on cell growth and invasion for bladder cancer, which may be mediated by diminishing the epithelial-to-mesenchymal transition and interleukin 6.

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“…Shiota et al (18) showed that FOXO3A inhibits UC invasiveness via Twist1, YB-1, and E-cadherin regulation. Zhuo et al (25) reported that upregulation of CSTP1 expression suppresses IL-6 expression by regulating the Akt/FoxO3a signaling pathway in UC. Zhu et al (26) showed that ATG7 overexpression promoted autophagic removal of FOXO3A in bladder carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

FOXO3A Expression in Upper Tract Urothelial Carcinoma

et al. 2021

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BackgroundEpidemiological studies have reported various results regarding whether FOXO3A is related to various carcinomas. However, the prognostic significance of FOXO3A in upper tract urothelial carcinoma (UTUC) remains unclear. The purpose of this study was to validate the correlation between FOXO3A expression and oncological outcomes in UTUC.MethodsThe expression levels of FOXO3A in 107 UTUC patients were examined by immunohistochemistry (IHC). We examined the prognostic role of FOXO3A by using the Cox proportional hazard model.ResultsThe results indicated that FOXO3A expression was notably decreased in UTUC tissue compared with control tissue. Decreased expression of FOXO3A was also related to advanced pathologic stage (P = 0.026), lymph node metastasis (P = 0.040), lymphovascular invasion (P < 0.001), and adjuvant therapy (P = 0.048). In addition, UTUC patients with low FOXO3A expression had a significantly shorter survival time, including both overall survival (OS) [hazard ratio (HR) 2.382, P = 0.004] and recurrence-free survival (RFS) (HR 2.385, P = 0.004), than those with high expression. Multivariate analyses showed that FOXO3A was a significant predictor for OS (HR 2.145, P = 0.014) and RFS (HR 2.227, P = 0.010) in UTUC patients.ConclusionOur results indicate that FOXO3A may be involved in the recurrence of UTUC and that it has certain clinical value in the therapeutic targeting and prognostic evaluation of UTUC.

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CSTP1 inhibits IL-6 expression through targeting Akt/FoxO3a signaling pathway in bladder cancer cells

Cited by 13 publications

References 40 publications

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Desloratadine, a Novel Antigrowth Reagent for Bladder Cancer

FOXO3A Expression in Upper Tract Urothelial Carcinoma

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