E2F1 drives chemotherapeutic drug resistance via ABCG2

Rosenfeldt, Mathias T.; Bell, L. Andrew; Long, Jaclyn; O’Prey, Jim; Nixon, Colin; Roberts, Fiona; Dufès, Christine; Ryan, Kevin M.

doi:10.1038/onc.2013.470

Cited by 41 publications

(26 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…E2F1 plays an important role in regulating development, differentiation, proliferation, cellular signal transduction, and apoptosis (9)(10)(11)(12). Certain studies reported that E2F1 disrupts a range of pathways in numerous cancers and is closely correlated with clinical parameters (13)(14)(15). We had also previously identified that E2F1 is upregulated in ccRCC progression (16).…”

Section: Introductionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

View full text Add to dashboard Cite

The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

show abstract

Section: Introductionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Yoshihara et al also showed that28 p21 and BAX expressions could be increased and the apoptosis caused by ADR also enhanced by decreasing intracellular E2F1 expression. Rosenfeldt et al found that E2F1 could increase the resistance to chemotherapeutic drugs by regulating ABCG2 expression level in the cells 29. Altogether, these results indicated that the high expression of E2F was one of the factors improving tumor drug resistance and could be a potential target for regulating tumor cells’ drug resistance.…”

Section: Discussionmentioning

confidence: 95%

Targeted regulation of MiR-98 on E2F1 increases chemosensitivity of leukemia cells K562/A02

Huang¹,

Hong²,

Hu³

et al. 2017

OTT

View full text Add to dashboard Cite

BackgroundmiRNA is a microRNA that negatively regulates protein expression at post-transcriptional or translational level. It is widely involved in the pathogenesis of tumors. miR-98 belongs to the let-7 family, and its overexpression can increase the sensitivity to drugs in solid cancer cells. However, the function of miR-98 in leukemia is still unclear. In this study, the effect of miR-98 on drug resistance and proliferation of leukemia cells were investigated.MethodsReal-time quantitative polymerase chain reaction analyzed the expression difference between miR-98 and E2F1 in leukemia cell lines, K562 and K562/A02. The downstream target gene of miR-98 was predicted by TargetScan; K562/A02 was transiently transfected with miR-98 mimic to upregulate the expression of miR-98; real-time quantitative polymerase chain reaction and Western blot were used to analyze the expression alterations of E2F1; cell counting kit-8 was used to evaluate the influence on K562/A02 proliferation and sensitivity to chemotherapeutic drugs; meanwhile, Western blot was used to analyze the expression of p21, Bax, matrix metalloproteinase 9 and ABCG2 proteins.ResultsE2F1 is one of the target genes of miR-98 proved by bioinformatics. Compared with the K562, the level of miRNA-98 expression was decreased in K562/A02, but the level of E2F1 expression was upregulated. Leukemia cell line K562/A02 was transfected with miR-98 mimic to upregulate the expression of miR-98, the expression of E2F1 was significantly decreased. After upregulating the miR-98 expression in K562/A02, the proliferation was weakened, and the sensitivity to chemotherapy was increased. Western blot showed that upregulated miR-98 expression increased the levels of p21 and BAX proteins in K562/A02 cells, and decreased the levels of matrix metalloprotease 9 and ABCG2 proteins, which were significantly different compared with those before miR-98 mimic transfection.ConclusionIn the leukemia drug-resistant cell line K562/A02, the targeted upregulated expression of miR-98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression. miR-98 might be a potential target for overcoming leukemia multidrug resistance.

show abstract

“…We suppose that the expression and activity of BCRP in cBCRP cells is not mediated through Akt signalling. a recent study identified the transcription factor e2F1, implicated in various cellular functions, as another possible activator of BCRP expression in various human lung cancer cell lines (23). Moreover, Rosenfeld et al (23) revealed that the E2F-BCRP axis suppresses chemotherapy-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

“…a recent study identified the transcription factor e2F1, implicated in various cellular functions, as another possible activator of BCRP expression in various human lung cancer cell lines (23). Moreover, Rosenfeld et al (23) revealed that the E2F-BCRP axis suppresses chemotherapy-induced cell death. Another important fact corresponding with our results is the attenuation of this resistance via BCRP inhibition.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of BCRP and anti-apoptotic proteins by proadifen (SKF-525A) is responsible for the enhanced mitoxantrone accumulation and toxicity in mitoxantrone-resistant human promyelocytic leukemia cells

Hiľovská

Jendželovský

Jendželovská

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. Drugs inhibiting these transporters have been shown to increase the anti-proliferative properties of chemotherapeutics. As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). Because mitoxantrone (MTX) is a strong BCRP substrate and is often used in the treatment of leukemia, we investigated the effect of 24 h proadifen pre-treatment on the cytotoxicity of MTX in leukemic cell lines that are sensitive to MTX (HL-60) and MTX-resistant ABCG2-overexpressing subclone (cBCRP). We show for the first time that proadifen is able to enhance the cytotoxic properties of MTX in cBCRP cells, particularly through the inhibition of BCRP expression and activity. This proadifen-MTX synergism was also mediated by the inhibition of various cellular proteins engaged in apoptosis, including Mc-1, Bcl-xL, survivin and activation of procaspase-3. Proadifen also decreased the expression of γH2AX, which is involved in the recruitment of reparation proteins. Moreover, the inhibition of DNA damage repair proteins Ku86 and B23 after proadifen treatment indicate a possible role of proadifen in DNA repair blockage, thus suppressing the reparation rate of MTX-induced DSBs.

show abstract

E2F1 drives chemotherapeutic drug resistance via ABCG2

Cited by 41 publications

References 27 publications

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Targeted regulation of MiR-98 on E2F1 increases chemosensitivity of leukemia cells K562/A02

Downregulation of BCRP and anti-apoptotic proteins by proadifen (SKF-525A) is responsible for the enhanced mitoxantrone accumulation and toxicity in mitoxantrone-resistant human promyelocytic leukemia cells

Contact Info

Product

Resources

About