Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A

Wang, Zhuoying; Wang, Chongren; Zuo, Dongqing; Zhang, Tao; Yin, Fei; Zhou, Zifei; Wang, Hongsheng; Xu, Jing; Mao, Min; Wang, Gangyang; Hua, Yingqi; Sun, Wei; Cai, Zhengdong

doi:10.7150/ijbs.30168

Cited by 28 publications

(29 citation statements)

References 31 publications

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“…[15][16][17][18][19] Further research has demonstrated that the attenuation of STAT3 phosphorylation promotes apoptosis and chemosensitivity in MG-63, U2OS and HOS cells. 20 However, the precise role of the IL-6/STAT3 pathway in modulating the stemness properties of osteosarcoma has yet to be elucidated.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…For example, Ye et al found that NVP‐TAE684, a kinase inhibitor, could inhibit MDR1 function and reverse MDR1-mediated chemoresistance in osteosarcoma 13 . Using the same doxorubicin-resistant cell lines, Wang and colleagues demonstrated that the transcription factor STAT3 (signal transducer and activator of transcription 3) could activate MDR1 expression and that attenuation of STAT3 phosphorylation induced apoptosis and increased chemosensitivity 14 .…”

Section: Introductionmentioning

confidence: 99%

Targeting the CtBP1-FOXM1 transcriptional complex with small molecules to overcome MDR1-mediated chemoresistance in osteosarcoma cancer stem cells

et al. 2021

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Chemoresistance is a major barrier for the chemotherapy of osteosarcoma. The induction of multidrug resistance protein 1 (MDR1), an ATP-dependent transporter, can efflux anti-cancer drugs, thereby decreasing chemosensitivity. However, an actual involvement of MDR1 in the chemoresistance of osteosarcoma cells has not been established. We obtained two cisplatin (CDDP)-resistant osteosarcoma cancer stem cell (CSC) lines using sphere formation medium supplemented with CDDP. These two CDDP-resistant CSC cell lines showed substantial cell proliferation, colony formation, cell invasion, and in vivo tumor growth in the presence of CDDP. Microarray analysis revealed that three genes, MDR1 , FOXM1 (forkhead box M1), and CtBP1 (C-Terminal binding protein 1), showed significant overexpression in both cell lines. Mechanistically, CtBP1 assembled with FOXM1 to form a transcriptional complex, which docked onto the MDR1 promoter to activate MDR1 expression. Knockdown or inhibition of the CtBP1-FOXM1 components with specific small molecules, including NSM00158 and NSC95397 for CtBP1 and RCM1 for FOXM1, significantly repressed MDR1 expression. Administration of these three small molecules also significantly inhibited tumor growth in mouse tumor xenograft model. The MDR1-mediated chemoresistance could be reversed by NSM00158 and RCM1. Collectively, our data revealed that the CtBP1-FOXM1 complex activated MDR1 expression and that targeting this complex with their specific inhibitors could reverse MDR1-mediated chemoresistance both in vitro and in vivo . Our results indicate a new therapeutic strategy for overcoming chemoresistance during osteosarcoma treatment.

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“…P-gp, also known as multidrug resistance protein 1 (MDR1), which is encoded by ATP-binding cassette subfamily B member 1(ABCB1), contributes to chemoresistance in various kinds of cancer (21). Wang et al (22)demonstrated that Raddeanin A restored doxorubicin chemosensitivity in OS drug-resistant U2OSR and KHOSR cells by downregulating MDR1. To further identify whether MDR1/p-gp is involved in CXCR4-mediated doxorubicin resistance, western blotting was utilized to detect the changes of p-gp expression after CXCR4 regulation.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Blockade Enhances The Sensitivity Of Osteosarcoma To Doxorubicin By Inducing Autophagic Cell Death Via PI3K-Akt-Mtor Pathway Inhibition

Zhou

et al. 2020

Preprint

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Background: Doxorubicin is one of the most frequent used chemotherapy drugs in the treatment of osteosarcoma (OS), but the emergence of chemoresistance often leads to its treatment failure. CXCR4 has been proved to regulate osteosarcoma progression and metastasis, however whether CXCR4 is also implicated in OS chemoresistance and its molecular mechanisms have not yet been fully elucidated. In this study, we investigated CXCR4-mediated autophagy for OS chemotherapy. Methods: Cell viability, western blot and apoptosis were performed to evaluate doxorubicin resistance after CXCR4 regulation (downregulation or upregulation) and treatment with autophagy modulators (bafilomycin A1 or rapamycin) in two OS cell lines (LM8 and Dunn). Autophagy-related proteins (Beclin1 and LC3B) detected by western blot, autophagosomes and autolysosomes observed by transmission electron microscopy, and autophagic flux monitored by confocal microscopy were utilized to comprehensively assess autophagy level changes. A C3H mouse osteosarcoma orthotopic model was established to determine anti-tumor effect of CXCR4 antagonist AMD3100 and doxorubicin in vivo.Results: CXCR4 inhibition enhanced doxorubicin-induced apoptosis by reducing p-glycoprotein, while CXCR4 overexpression promoted OS doxorubicin resistance. Moreover, CXCR4 inhibition combined with or without doxorubicin increased Beclin1 and LC3B expression, numbers of autophagosome and autolysosome, and induced autophagic flux activation by suppressing PI3K-Akt-mTOR pathway. In addition, pretreatment with autophagy inhibitor bafilomycin A1 attenuated CXCR4 abrogation-induced cell death. Finally, CXCR4 antagonist AMD3100 synergistically reinforced anti-tumor effect of doxorubicin in orthotopic OS mouse model. Conclusions: This study revealed CXCR4 inhibition sensitizes OS to doxorubicin by inducing autophagic cell death. Targeting CXCR4/autophagy axis may be a promising therapeutic strategy to overcome OS chemotherapy resistance.

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Attenuation of STAT3 Phosphorylation Promotes Apoptosis and Chemosensitivity in Human Osteosarcoma Induced by Raddeanin A

Cited by 28 publications

References 31 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>

Targeting the CtBP1-FOXM1 transcriptional complex with small molecules to overcome MDR1-mediated chemoresistance in osteosarcoma cancer stem cells

CXCR4 Blockade Enhances The Sensitivity Of Osteosarcoma To Doxorubicin By Inducing Autophagic Cell Death Via PI3K-Akt-Mtor Pathway Inhibition

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