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

Abstract

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.

Oxyresveratrol induces apoptosis and inhibits cell viability via inhibition of the STAT3 signaling pathway in Saos‑2 cells

“…The il-6-JaK-STaT3 signaling axis contributes to the pathogenesis of myeloma cells by preventing apoptosis (50). By blocking the il-6-oPn-STaT3 signaling pathway, the viability and tumorigenesis of osteosarcoma cells are inhibited (21). This is consistent with the findings of the present study, which demonstrated that compared with in the control group, the phosphorylation of STaT3 was attenuated by oreS treatment in Saos-2 cells.…”

“…5a and c). oPn is regulated by STaT3 signaling, which is involved in osteosarcoma pathogenesis (21). compared with those of the untreated group, treatment with ORES significantly decreased the expression levels of oPn ( Fig.…”

“…Therefore, STaT3 may have an important therapeutic and prognostic value in osteosarcoma. in addition, STaT3 is directly involved in transcriptional regulation of osteopontin (oPn) (20), and increased oPn expression levels serve a critical role in osteosarcoma, which is a potential biomarker and promising drug target for osteosarcoma (21).…”

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

“…For example, cinobufagin was found to promote cell cycle arrest at the G2/M phase and apoptosis in hepatocellular carcinoma and esophageal squamous cell carcinoma by increasing the expression levels of pro-apoptotic p73 and BAX [39,40]. Cinobufagin was found to induce apoptosis in osteosarcoma cancer cells by suppressing cancer-promoting signaling pathways such as STAT3, Notch and NF-kB, and activating mitochondria-mediated apoptosis pathways [41][42][43][44]. The anti-angiogenic effect of cinobufagin by suppressing the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF1α) signaling pathways has also been observed in colorectal cancer [45].…”

TRIP6 regulates the proliferation, migration, invasion and apoptosis of osteosarcoma cells by activating the NF‑κB signaling pathway

“…Os accounts for ~20% of primary malignant bone tumors and 0.5% of malignant tumors (2). Os tends to occur in the epiphyseal region where there is an abundant blood supply, thus the incidence of hematogenous metastasis is high, occurs early and progresses quickly (3). Previous studies have shown that, if not treated in time, 80% of patients with Os will develop lung metastases, which is often fatal (4)(5)(6).…”