STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

Khodarev, Nikolai N.; Roach, Paul D.; Pitroda, Sean P.; Golden, Daniel W.; Bhayani, Mihir K.; Shao, Michael Y.; Darga, Thomas E.; Beveridge, Mara; Sood, Ravi F.; Sutton, Harold G.; Beckett, Michael A.; Mauceri, Helena J.; Posner, Mitchell C.; Weichselbaum, Ralph R.

doi:10.1371/journal.pone.0005821

Cited by 113 publications

(96 citation statements)

References 60 publications

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“…Constitutive high expression of IFN/STAT1-regulated genes protected tumor cells from the cytotoxic effect of cisplatin and fludarabine (46,47). In human head and neck squamous, radiation-resistant tumors overexpressed a substantial number of genes inducible by IFNs or related to their signaling pathway (48)(49)(50). The IFN-related DNA damage resistance signature was also associated with resistance to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Luszczek

Cheriyath

Mekhail

et al. 2010

Molecular Cancer Therapeutics

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Because epigenetic inhibitors can reduce cancer cell proliferation, we tested the hypothesis that concurrent inhibition of histone acetylation and DNA methylation could synergistically reduce the viability of small cell lung cancer (SCLC) cells. Sub-IC 50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine (5-AZA-dC) and the histone deacetylase (HDAC) inhibitors (LBH589 or MGCD0103) synergistically reduced the proliferation of five of nine SCLC cell lines. Loss of viability of sensitive SCLC cells did not correlate with the inhibition of either DNMT1 or HDACs, suggesting nonepigenetic mechanisms for synergy between these two classes of epigenetic modulators. Because combinations of 5-AZA-dC and HDAC inhibitors had marginal effects on the apoptosis index, Comet assay was undertaken to assess DNA damage. MGCD0103 and 5AZA-dC cotreatment augmented DNA damage in SCLC cells, resulting in increased tail length and moment in Comet assays by 24 hours in sensitive cell lines (P < 0.01). Consistent with augmented DNA damage, combination of a DNMT and HDAC inhibitor markedly increased the levels of phospho-H2A.X in sensitive cells but not in resistant ones. Comparison of basal gene expression between resistant and sensitive cells identified markedly higher basal expression of IFN-stimulated genes in the resistant cell lines, suggesting that IFN-stimulated gene expression may determine SCLC cell sensitivity to epigenetic modulators or other DNA damaging agents. Mol Cancer Ther; 9(8); 2309-21. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

“…Cell numbers before and after the treatment were determined by generating standard curves with known numbers of nontreated cells. An IC 50 value was calculated based on the viability curve. The multiple drug effect analysis of Chou and Talalay (24) was used to determine the pharmacologic interaction between 5-AZA-dC and HDAC inhibitors.…”

Section: Viability Assaymentioning

confidence: 99%

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Luszczek

Cheriyath

Mekhail

et al. 2010

Molecular Cancer Therapeutics

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“…Previous studies showed that Stat1 mediates the expression of a set of IFNinducible genes known as IFN-related DNA damage-resistance signature, which renders different tumor types increasingly resistant to chemotherapy and radiation therapies (62)(63)(64)(65). More recent work demonstrated that unphosphorylated Stat1 mediates the induction of genes that protect cells from virus infection or DNA damage in response to prolonged treatment with IFN-β (2).…”

Section: Stat1 Protects Cells From the Antiproliferative Effects Of Amentioning

confidence: 99%

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang

Patsis

Koromilas

2015

Proc. Natl. Acad. Sci. U.S.A.

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The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

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“…In the nucleus, STAT1 binds to the cognate transcriptional elements and activates IFN-inducible genes, leading to growth arrest and cell death [23,24]. On the other hand, STAT1 overexpression is associated with tumor progression [25,26] and acquisition of RT resistance [19,25,27,28]. Khodarev et al reported that RT-resistant squamous cell carcinoma (SCC) cells overexpressed STAT1 [27] and suppression of STAT1 recovered RT sensitivity [28].…”

Section: Discussionmentioning

confidence: 99%

979 Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1

Kijima¹,

Koga²,

Fujii³

et al. 2013

European Urology Supplements

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Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1.

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STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

Cited by 113 publications

References 60 publications

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

979 Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1

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