A Novel Human Stress Response-Related Gene with a Potential Role in Induced Radioresistance

Robson, Tracy; Joiner, M. C.; Wilson, GD; McCullough, W.; Price, ME; Logan, Ian R.; Jones, Heddwyn; McKeown, Stephanie; Hirst, DG

doi:10.2307/3580140

Cited by 51 publications

(44 citation statements)

References 34 publications

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“…The final two data sets, GSE1378 and GSE2990 (from tamoxifen-treated patients), did not show any correlation, but the patient numbers are lower, especially in the GSE1378 data set, which also used a different microarray platform and microdissected tumor cells rather than whole tumor tissues. A lack of concordance between data sets is a common feature in microarray studies (40), but this could also be because GSE2034 and GSE1378 patients were treated with radiotherapy and FKBPL has previously been shown to be regulated by radiation (10,11). Furthermore, the data sets showing no correlation were generally smaller in size; the number of samples is known to affect statistical significance in this type of study.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that it belongs to the immunophilin/FKBP protein family as a consequence of the presence of COOH-terminal tetratricopeptide repeat domains (TPR) and a partial peptidyl-prolyl cis-trans isomerase (PPIase) domain (10,11). The TPR domains of immunophilin proteins are particularly important for binding to the molecular chaperone Hsp90 (12).…”

Section: Introductionmentioning

confidence: 99%

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FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

et al. 2010

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The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor α (ERα) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERα phosphorylation on Ser 118 in response to 17β-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

et al. 2010

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“…The major effector genes identified in the radiation-induced response include RAF1, CDKNIA (p21), GADD45A (GADD45), 14-3-3 σ (a member of the YWHA family), BAX, TNFRSF (Fas/APO1), TNFRSF 10B (KILLER/DR5), PIG, THBS1 (TSP1), IGFBP3 and DIR1. These radiation-responsive effector genes and their control factors play key roles in the cellular response to radiationinduced stress by modulating cell cycle checkpoints, apoptosis and DNA repair, which enhance cell survival (3,(8)(9)(10)(12)(13)(14)(15)(16). Changes in the mRNA expression levels were reported by cDNA microarray data targeting radiation-responsive genes in human breast cancer cells (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Protein expression pattern in response to ionizing radiation in MCF-7 human breast cancer cells

Jung

Lee

et al. 2011

Oncology Letters

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Abstract. Breast cancer is one of the most common types of cancer in women and is highly treatable by radiotherapy. However, repeated exposure to radiation results in tumor cell resistance. Understanding the molecular mechanisms involved in the response of tumors to γ-irradiation is important for improving radiotherapy. For this reason, we aimed to identify radiation-responsive genes at the protein level. In the present study, we observed differentially expressed proteins using 2D-PAGE and MALDI-TOF-MS for the global analysis of protein expression patterns in response to ionizing radiation (IR). When the expression patterns of proteins were compared to a control gel, numerous spots were found that differed greatly. Among them, 11 spots were found to be significantly different. One set of proteins (GH2, RGS17, BAK1, CCNH, TSG6, RAD51B, IGFBP1 and CASP14) was upregulated and another set of proteins (C1QRF, PLSCR2 and p34 SE1-1 ) was downregulated after exposure to γ-rays. These proteins are known to be related to cell cycle control, apoptosis, DNA repair, cell proliferation and other signaling pathways.

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“…FK506-binding protein like (FKBPL) is a divergent member of the FK506-binding protein family. FKBPL was identified as having a role in the response of cells to radiation (21,22). In a complex with Hsp90, FKBPL stabilizes p21 (23) and regulates estrogen receptor (ER), androgen receptor, and glucocorticoid receptor signaling (2,24,25).…”

Section: Introductionmentioning

confidence: 99%

Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway

McClements

Yakkundi

Papaspyropoulos

et al. 2013

Clinical Cancer Research

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Purpose: FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC).Experimental Design: Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment AE other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence.Results: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESAtions in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01-mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo-and radiotherapyinduced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling. Conclusions: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial.

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A Novel Human Stress Response-Related Gene with a Potential Role in Induced Radioresistance

Cited by 51 publications

References 34 publications

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

Protein expression pattern in response to ionizing radiation in MCF-7 human breast cancer cells

Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway

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