Oestrogen‐related receptor alpha mediates chemotherapy resistance of osteosarcoma cells via regulation of <scp>ABCB</scp>1

Chen, Yantao; Zhang, Kun-Shui; Yang, Li; Guo, Ruiyun; Zhang, Kelin; Zhong, Guifang; He, Qing

doi:10.1111/jcmm.14123

Cited by 24 publications

(24 citation statements)

References 42 publications

(101 reference statements)

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“…In addition, inhibition of ERRα could reverse its promoting effects and trigger programmed cell death and cellular cycle arrested in PC cells. Furthermore, recent studies imply that ERRα has been participating in chemoresistance of many tumors, more importantly, targeted inhibition of ERRα could restore chemosensitivity of those cancer cells [11][12][13][14]. Taken together, these findings indicated that ERRα might be a treatment target for PC.…”

Section: Introductionmentioning

confidence: 91%

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Liu¹,

Liang²,

Yang³

et al. 2022

Int. J. Med. Sci.

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Pancreatic cancer (PC) is one of the most fatal and chemoresistant malignancies with a poor prognosis. The current therapeutic options for PC have not achieved satisfactory results due to drug resistance. Therefore, it is urgent to develop novel treatment strategies with enhanced efficacy. This study sought to investigate the anticancer effect of gemcitabine and XCT790, an estrogen-related receptor alpha (ERRα) inverse agonist, as monotherapies or in combination for the treatment of PC. Here we demonstrated that the drug combination synergistically suppressed PC cell viability, its proliferative, migratory, invasive, apoptotic activities, and epithelial-to-mesenchymal transition (EMT), and it triggered G0/G1 cell cycle arrest and programmed cell death in vitro. In addition, in vivo assays using xenograft and mini-PDX (patient-derived xenograft) models further confirmed the synergistic antitumor effect between gemcitabine and XCT790 on PC. Mechanistically, gemcitabine and XCT790 suppressed PC by inhibiting ERRα and MEK/ERK signaling pathway. In conclusion, our current study demonstrated for the first time that gemcitabine combined with XCT790 displayed synergistic anticancer activities against PC, suggesting that their combination might be a promising treatment strategy for the therapy of PC.

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Section: Introductionmentioning

confidence: 91%

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Liu¹,

Liang²,

Yang³

et al. 2022

Int. J. Med. Sci.

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“…Unluckily, only in few cases the snoRNA host genes are known, limiting the number of druggable targets. At preclinical level, several siRNA- or shRNA-based tools have successfully reversed Dox resistance in osteosarcoma, e.g., by directly silencing Pgp [ 59 , 60 ] or by silencing transcription factors, as estrogen-related receptor α (ERRα) that up-regulates Pgp [ 61 ] or nuclear factor (erythroid-derived 2)-like 2 (NRF2) that mediates resistance to oxidative stress and up-regulates multiple ABC transporters [ 62 ]. The major advantage of these approaches is that they can achieve high specificity in targeting a gene or a pathway involved in chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

Godel

Morena

Ananthanarayanan

et al. 2020

IJMS

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Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas.

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“…The involvement of ERRα in drug resistance has been widely studied in breast cancer and osteosarcoma (44)(45)(46)(47)(48). However, its role in PCa drug resistance was rarely examined.…”

Section: Discussionmentioning

confidence: 99%

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Huang

Shen

et al. 2020

Front. Oncol.

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Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

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Oestrogen‐related receptor alpha mediates chemotherapy resistance of osteosarcoma cells via regulation of ABCB1

Cited by 24 publications

References 42 publications

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer

Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

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