The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

Zheng, Peng; Zhang, Chun; Zhou, Wenjun; Wu, Chenchun; Zhang, Yi

doi:10.1002/jcp.26362

Cited by 29 publications

(30 citation statements)

References 34 publications

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“…Persistently active STAT3 has been identified in many human cancers and appears to be required for the continued growth or resistance to apoptosis of cultured human cancer cells. 20,25,41,42 In this study, phospho-JNK activation in- Additionally, several reports have demonstrated that there are interacting regions in STAT3 and c-Jun that participate in cooperative transcriptional activation. 14,18,19,43 These concepts support our finding that phospho-STAT3 was suppressed by the activation of phospho-JNK and phospho-c-Jun.…”

Section: Discussionmentioning

confidence: 65%

“…Our research team has reported that inhibition of STAT3 phosphorylation has beneficial clinical therapeutic effects on human osteosarcoma. Persistently active STAT3 has been identified in many human cancers and appears to be required for the continued growth or resistance to apoptosis of cultured human cancer cells . In this study, phospho‐JNK activation induced significant phospho‐STAT3 degradation.…”

Section: Discussionmentioning

confidence: 67%

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Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A ( RA ) is an active oleanane‐type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose‐ and time‐dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species ( ROS ) generation and JNK and ERK 1/2 activation. Apoptosis induction was evaluated by the activation of caspase‐3, caspase‐8, and caspase‐9 and poly‐ADP ribose polymerase ( PARP ) cleavage. RA ‐induced cell death was significantly restored by the ROS scavenger glutathione ( GSH ), the pharmacological inhibitor of JNK SP 600125, or specific JNK knockdown by sh RNA . Additionally, signal transducer and activator of transcription 3 ( STAT 3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH , SP 600125, and JNK ‐sh RNA . Further investigation showed that STAT 3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK /c‐Jun and STAT 3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 67%

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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“…While supporting the anticancer activity of RA that has been indicated in other cancer types, [19][20][21][22][23][24][25][26][27][28] our findings unveil a tissuespecific effect of RA in prostate cancer. That is to target AR-FL and AR-Vs.…”

Section: Discussionsupporting

confidence: 84%

“…18 Preclinical studies have indicated the antitumour activity of RA against gastric cancer, colorectal cancer, breast cancer, liver cancer, choriocarcinoma, glioblastoma and osteosarcoma. [19][20][21][22][23][24][25][26][27][28] In the present study, we sought to investigate the anticancer effect of RA in prostate cancer. We found that it could suppress the activity of both AR-FL and AR-Vs to inhibit the growth of prostate cancer cells at an in vivo achievable concentration.…”

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confidence: 99%

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

Xia

Bai

et al. 2019

J Cellular Molecular Medi

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Castration‐resistant progression of prostate cancer is a major cause of prostate cancer mortality, and increased expression and activity of the full‐length and the splice variants of androgen receptor (AR) have been indicated to drive castration resistance. Consequently, there is an urgent need to develop agents that can target both the full‐length and the splice variants of AR for more effective treatment of prostate cancer. In the present study, we showed that raddeanin A (RA), an oleanane‐type triterpenoid saponin, suppresses the transcriptional activities of both the full‐length and the splice variants of AR. This is attributable to their decreased expression as a result of RA induction of proteasome‐mediated degradation and inhibition of the transcription of the AR gene. We further showed the potential of using RA to enhance the growth inhibitory efficacy of docetaxel, the first‐line chemotherapy for prostate cancer. This study identifies RA as a new agent to target both the full‐length and the splice variants of AR and provides a rationale for further developing RA for prostate cancer treatment.

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“…However, in our study, PSTT was least sensitive to MTX among the drugs in the commonly used combination chemotherapy regimen EMA/EP. JEG-3/MTX and JEG-3R cells have been used as resistance models (27,28) to identify mechanism for chemotherapeutic resistance to MTX in choriocarcinoma (29) . JEG-3R showed more than 20-fold resistance compared to JEG-3/MTX.…”

Section: Discussionmentioning

confidence: 99%

Identification of cell cycle dependent methotrexate resistance in placenta site trophoblastic tumors

Zhang

Liu

et al. 2020

Preprint

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Background The purpose is to study the mechanism of chemotherapy resistance in Placental site trophoblastic tumor(PSTT).Methods We established PSTT cell lines by primary culture of a surgically resected PSTT tissues and identified the expression of immune-phenotype markers(HLA-G, β-catenin, CD146, Muc4, hPL, hCG) by immunofluorescence. We measured the IC50 value of methotrexate(MTX), etoposide(VP-16), actinomycin-D(Act-D), cisplatin(DDP), fluorouracil(5-FU) and paclitaxel(TAX) in PSTTs and used a special Mini patient-derived xenograft (Mini PDX) model to evaluate effectiveness of these drugs in vivo. Given that MTX is a cell cycle-dependent chemotherapeutic, we analyzed cell cycle characteristics of PSTT and choriocarcinoma cell lines by flow cytometry and then analyzed RNA profiles and WGS data of the PSTT cell lines to identify the potential mechanism.Results We identified the expression of HLA-G, β-catenin, CD146, hPL and hCG in PSTT cell lines. The IC50 value of MTX was 4.922 mg/ml in PSTT-1, 4.525 mg/ml in PSTT-2, 5.117 mg/ml in PSTT-3, 0.0166 µg/ml in JEG-3 cells (p༜0.001), and 0.01 µg/ml in JAR cells (p༜0.001), with nearly 50,000-fold increase in PSTTs than in choriocarcinoma, indicating that PSTTs are resistant to MTX in vitro. The Mini PDX model revealed that PSTTs are also resistant to MTX in vivo. Cell cycle analysis showed dysregulation of G1/S transition and cell cycle arrest in PSTT cell lines. RNA sequencing profile also identified cell cycle-associated genes which were differentially expressed in PSTT cells than in choriocarcinoma cell.Conclusions We found PSTTs are resistant to MTX in vitro and in vivo compared to choriocarcinoma. Mechanisms could be focused on dysregulation of the G1/S transition and cell cycle arrest.

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The STAT3/NFIL3 signaling axis‐mediated chemotherapy resistance is reversed by Raddeanin A via inducing apoptosis in choriocarcinoma cells

Cited by 29 publications

References 34 publications

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

Raddeanin A down‐regulates androgen receptor and its splice variants in prostate cancer

Identification of cell cycle dependent methotrexate resistance in placenta site trophoblastic tumors

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