Methotrexate-mediated inhibition of RAD51 expression and homologous recombination in cancer cells

Du, Liqing; Du, Xiaojiao; Bai, Jian-qiang; Wang, Yan; Yang, Qingshan; Wang, Xiaochun; Zhao, Peng; Wang, Hong; Liu, Qiang; Fan, Feiyue

doi:10.1007/s00432-011-1132-8

Cited by 14 publications

(11 citation statements)

References 27 publications

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“…We found that MTX treatment gave rise to significantly decreased RAD51 in choriocarcinoma cells, whereas the inhibitory effect was inconspicuous in MG63 cells. However, inconsistent with our results, RAD51 was reported to be dramatically suppressed by MTX in another osteosarcoma cell line HOS, perhaps due to different cell types and MTX treatment conditions 25. Our findings suggest that MTX-induced inhibition on RAD51 led to persistently unrepaired DSBs in choriocarcinoma cell, which consequently result in chemotherapeutic hypersensitivity.…”

Section: Discussioncontrasting

confidence: 99%

“…Besides HR, non-homologous end joining (NHEJ) is another repair pathway for DSB. There is evidence that NHEJ mutant cells are more sensitive to MTX compared to the parental ones, which is consistent with our results that MTX acts through inducing DSBs 25. However, there is evidence that the increased incidence of SPTs (hematologic malignancies, colorectal cancer, thyroid cancer, etc) after choriocarcinoma may be associated with MTX treatment 17.…”

Section: Discussionsupporting

confidence: 91%

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Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Xie

Zhao

Cai

et al. 2016

OTT

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ObjectiveThe objective of this study was to investigate the mechanism of sensitivity to methotrexate (MTX) in human choriocarcinoma cells regarding DNA damage response.MethodsTwo choriocarcinoma cancer cell lines, JAR and JEG-3, were utilized in this study. An MTX-sensitive osteosarcoma cell line MG63, an MTX-resistant epithelial ovarian cancer cell line A2780 and an MTX-resistant cervical adenocarcinoma cell line Hela served as controls. Cell viability assay was carried out to assess MTX sensitivity of cell lines. MTX-induced DNA damage was evaluated by comet assay. Quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of BRCA1, BRCA2, RAD51 and RAD52. The protein levels of γH2AX, RAD 51 and p53 were analyzed by Western blot.ResultsRemarkable DNA strand breaks were observed in MTX-sensitive cell lines (JAR, JEG-3 and MG63) but not in MTX-resistant cancer cells (A2780 and Hela) after 48 h of MTX treatment. Only in the choriocarcinoma cells, the expression of homologous recombination (HR) repair gene RAD51 was dramatically suppressed by MTX in a dose- and time-dependent manner, accompanied with the increase in p53.ConclusionThe MTX-induced DNA strand breaks accompanied by deficiencies in HR repair may contribute to the hypersensitivity to chemotherapy in choriocarcinoma.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 91%

Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Xie

Zhao

Cai

et al. 2016

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“…To further ensure the uptake of methotrexate by Hut78 cells, we investigated the mRNA expression level of the RAD51 gene under the same condition of methotrexate treatment. RAD51 was shown as a target of methotrexate effect . Consistent with that reported, we observed significant decrease in RAD51 mRNA expression on methotrexate‐treated Hut78 cells, in a time‐dependent manner ( P < 0.05, one‐way anova ; Fig.…”

Section: Resultssupporting

confidence: 90%

Aberrant expression of BCL11B in mycosis fungoides and its potential role in interferon‐induced apoptosis

Wang

Zhang

et al. 2013

The Journal of Dermatology

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BCL11B is a Kruppel-like C2H2-type zinc finger transcription factor, which has been associated with several human malignancies. Recent evidence showed that overexpressed BCL11B conferred chemoresistance to malignant T cells and that inhibiting BCL11B led to increased apoptosis, suggesting its potential pathogenic relevance in cutaneous T-cell lymphomas (CTCL), which were characterized by the resistance to chemotherapy-induced apoptosis. To investigate the expression pattern of BCL11B in different stages of mycosis fungoides (MF), quantitative reverse transcription polymerase chain reaction and immunohistochemistry were performed to compare the mRNA and protein expression among different stages of MF and benign inflammatory dermatoses (BID), respectively. BCL11B demonstrated significant upregulation in all stages of MF, compared with BID, in both mRNA expression level and protein level. In addition, BCL11B expression increased with advancing lesion tumor stage and overall disease stage. Further, to evaluate the dynamic expression of BCL11B under CTCL-directed treatment, BCL11B expression and cell apoptosis were evaluated after interferon (IFN)-α-2b and methotrexate treatment on CTCL cell line Hut78 cells. IFN-α-2b, but not methotrexate, induced BCL11B inhibition and cell apoptosis, suggesting that BCL11B may play important roles in the anti-CTCL effect of IFN-α-2b. In conclusion, our study demonstrated the overexpression of BCL11B in MF lesions and its potential relevance to disease progression. In addition, we provided evidence for BCL11B inhibitory approaches as a potential treatment to target chemoresistant tumor cells in advanced MF.

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“…There are fewer reports regarding the association of methotrexate with DNA repair systems. Nonetheless, methotrexate has been shown to affect the homologous recombination repair of DNA DSBs by controlling the expression of HR related genes and suppressing the proper assembly of HR recombination-directed subnuclear foci [49]. …”

Section: Discussionmentioning

confidence: 99%

Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate

et al. 2017

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Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) comprise the majority of CTCL, a heterogenous group of non-Hodgkins lymphomas involving the skin. The CTCL’s resistance to chemotherapy and the lack of full understanding of their pathogenesis request further investigation. With the view of a more targeted therapy, we evaluated in vitro the effectiveness of bortezomib and methotrexate, as well as their combination in CTCL cell lines, regarding apoptosis induction. Our data are of clinical value and indicate that the bortezomib/methotrexate combinational therapy has an inferior impact on the apoptosis of CTCL compared to monotherapy, with bortezomib presenting as the most efficient treatment option for SS and methotrexate for MF. Using PCR arrays technology, we also investigated the alterations in the expression profile of genes related to DNA repair pathways in CTCL cell lines after treatment with bortezomib or methotrexate. We found that both agents, but mostly bortezomib, significantly deregulate a large number of genes in SS and MF cell lines, suggesting another pathway through which these agents could induce apoptosis in CTCL. Finally, we show that SS and MF respond differently to treatment, verifying their distinct nature and further emphasizing the need for discrete treatment approaches.

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Methotrexate-mediated inhibition of RAD51 expression and homologous recombination in cancer cells

Abstract: These results demonstrate that methotrexate can affect homologous recombination repair of DNA double-strand breaks by controlling the expression of homologous recombination-related genes and suppressing the proper assembly of homologous recombination-directed subnuclear foci.

Cited by 14 publications

References 27 publications

Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Aberrant expression of BCL11B in mycosis fungoides and its potential role in interferon‐induced apoptosis

Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate

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