Cross-Linking of Signal Transducer and Activator of Transcription 3—A Molecular Marker for the Photodynamic Reaction in Cells and Tumors

Henderson, Barbara W.; Daroqui, Cecilia; Tracy, Erin; Vaughan, Lurine A.; Loewen, Gregory; Cooper, Mary Anne

doi:10.1158/1078-0432.ccr-06-2950

Cited by 37 publications

(45 citation statements)

References 22 publications

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“…Because it has been proposed that cell transformation induces an intrinsic resistance program to chemotherapy (56), we speculate that cdk5-STAT3 provides cancer cells with intrinsic resistance capacities due to enhanced Eme1 expression and that this a corollary of cell transformation. We propose that the early detection on tumor biopsies of the cdk5-STAT3 oncogenic pathway, both of its phosphorylation status and of its target genes, will provide oncologists with a resistance profile indicative of tumors that will fail to respond to chemotherapy (15,57). In addition, we also propose that STAT3 inhibitors, which are emerging as new targeted cancer therapies (2,57,58) should be tested in clinical trials in combination with irinotecan to reduce DNA repair and enhance the efficiency of genotoxic treatments.…”

Section: Discussionmentioning

confidence: 99%

The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition

Courapied¹,

Sellier²,

Trécesson

et al. 2010

Journal of Biological Chemistry

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The STAT3 transcription factors are cytoplasmic proteins that induce gene activation in response to growth factor stimulation. Following tyrosine phosphorylation, STAT3 proteins dimerize, translocate to the nucleus, and activate specific target genes involved in cell-cycle progression. Despite its importance in cancer cells, the molecular mechanisms by which this protein is regulated in response to DNA damage remain to be characterized. In this study, we show that STAT3 is activated in response to topoisomerase I inhibition. Following treatment, STAT3 is phosphorylated on its C-terminal serine 727 residue but not on its tyrosine 705 site. We also show that topoisomerase I inhibition induced the up-regulation of the cdk5 kinase, a protein initially described in neuronal stress responses. In co-immunoprecipitations, cdk5 was found to associate with STAT3, and pulldown experiments indicated that it associates with the C-terminal activation domain of STAT3 upon DNA damage. Importantly, the cdk5-STAT3 pathway reduced DNA damage in response to topoisomerase I inhibition through the up-regulation of Eme1, an endonuclease involved in DNA repair. ChIP experiments indicated that STAT3 can be found associated with the Eme1 promoter when phosphorylated only on its serine 727 residue and not on tyrosine 705. We therefore propose that the cdk5-STAT3 oncogenic pathway plays an important role in the expression of DNA repair genes and that these proteins could be used as predictive markers of tumors that will fail to respond to chemotherapy.Signal transducer and activator of transcription 3 (STAT3) 3 proteins are cytoplasmic transcription factors that translocate into the nucleus following growth factor stimulation. In contrast to normal cells where its phosphorylation is only transient, constitutive activation of STAT3 has been reported in several primary cancers and tumor cell lines (1-3). This abnormal activation is due to oncogenic kinases such as epidermal growth factor receptor, Her2/Neu, src, or bcr-abl, which induce STAT3 activation through phosphorylation of its tyrosine 705 residue (4). This phosphorylation allows the nuclear translocation and DNA binding of the STAT3 dimer and the up-regulation of several genes involved in cell-cycle and cell survival such as cyclin D1, Myc, or bclxl. The up-regulation of these cancer genes mediates the oncogenic activity of STAT3 and its ability to transform cells (5).

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Section: Discussionmentioning

confidence: 99%

The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition

Courapied¹,

Sellier²,

Trécesson

et al. 2010

Journal of Biological Chemistry

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“…Photodynamic therapy reduced the STAT3 response to IL-6 by 90%, but that to Hyper-IL-6 only by 30%. The presence of crosslinked STAT3 complexes, which are known to correspond to absorbed PDT dose (Liu et al, 2004;Henderson et al, 2007), indicated that the individual cultures within each experimental group had received comparable PDT exposure. Taken together, this suggests a preferential PDTmediated inactivation of IL-6Ra over gp130, the latter still being able to engage the IL-6/sIL-6Ra complex.…”

Section: Conditioned Medium From Pdt-treated Hela Cells Induces Macromentioning

confidence: 99%

Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling

et al. 2007

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Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumour cells are subject to regulation by IL-6 and whether this regulation could contribute to tumour control by PDT. We demonstrate in epithelial tumour cells that while the action of IL-6 cytokines through their membrane receptors is attenuated, regulation by IL-6 via trans-signalling is established. Soluble interleukin-6 receptor-a (IL-6Ra) (sIL-6Ra) and IL-6 were released by leucocytes in the presence of conditioned medium from PDT-treated tumour cells. Cells that had lost their membrane receptor IL-6Ra due to PDT responded to treatment with the IL-6R -IL-6 complex (Hyper-IL-6) with activation of signal transducers and activator of transcription (STAT3) and ERK. Photodynamic therapy-treated cells, which were maintained during post-PDT recovery in presence of IL-6 or Hyper-IL-6, showed an enhanced suppression of proliferation. Cytokine-dependent inhibition of proliferation correlated with a decrease in cyclin E, CDK2 and Cdc25A, and enhancement of p27kip1 and hypophosphorylated Rb. The IL-6 trans-signalling-mediated attenuation of cell proliferation was also effective in vivo detectable by an improved Colon26 tumour cure by PDT combined with Hyper-IL-6 treatment. Prevention of IL-6 trans-signalling using soluble gp130 reduced curability. The data suggest that the post-PDT tumour milieu contains the necessary components to establish effective IL-6 trans-signalling, thus providing a means for more effective tumour control.

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“…The level of STAT3 crosslinking in tumor tissue subjected to PDT in situ was determined by excising the tumor immediately following light treatment, mincing tumor tissue and extracting proteins by sonication in RIPA buffer. Aliquots of cleared extracts, containing 20 µg proteins, were separated under denatured condition on 6% SDS polyacrylamide gels and analyzed by immunoblotting for the level of homodimeric STAT3 relative to total STAT3 as reported previously [22,52].…”

Section: Stat3 Crosslinkingmentioning

confidence: 99%

“…The crosslinking of STAT3 is strictly proportional to the delivered light dose and PS dose and thus can be used as a molecular marker for the cumulative photoreaction [22]. Quantification of vascular parameters before and during PDT is desired for monitoring and optimizing the PDT response that is manifested by the level of STAT3 crosslinking at the end of light treatment.…”

Section: Introductionmentioning

confidence: 99%

Blood flow dynamics during local photoreaction in a head and neck tumor model

et al. 2015

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We have applied continuous blood flow dynamics, quantified with diffuse correlation spectroscopy (DCS), in investigating photodynamic therapy (PDT) induced local photoreaction in a head and neck tumor model. Photoclor (0.47 µmol/kg) was intravenously administered 24 h before PDT. Two types of fluence rates were implemented: Low fluence rate (14 mW/cm 2 ) and high fluence rate (75 mW/cm 2 ). The total delivered fluence was 100 J/cm 2 for both types. We observed that PDT induced substantial vascular shut down in both types. While the shutdown was persistent in tumors exposed to low fluence rate PDT, the shutdown was transient in tumors exposed to high fluence PDT. Loss of microvascular structures was confirmed by the microscopic analyses of tumor section following immunostaining for CD31. Blood flow dynamics related metrics were also strongly correlated with crosslinking of STAT3, a molecular marker of photoreaction. STAT3 analysis indicated that low fluence rate yields a substantially higher photoreaction, and thus, a more effective PDT. Our results indicate that non-invasive blood flow measurements can monitor the efficacy of PDT in real-time and potentially provide a feedback for its optimization.

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Cross-Linking of Signal Transducer and Activator of Transcription 3—A Molecular Marker for the Photodynamic Reaction in Cells and Tumors

Cited by 37 publications

References 22 publications

The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition

The cdk5 Kinase Regulates the STAT3 Transcription Factor to Prevent DNA Damage upon Topoisomerase I Inhibition

Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling

Blood flow dynamics during local photoreaction in a head and neck tumor model

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