STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy <i>in vitro</i> and <i>in vivo</i>

Spitzner, Melanie; Roesler, Birte; Bielfeld, Christian; Emons, Georg; Gaedcke, Jochen; Wolff, Hendrik A.; Rave-Fränk, Margret; Krämer, Frank; Beißbarth, Tim; Kitz, Julia; Wienands, Jürgen; Ghadimi, B. Michael; Ebner, Reinhard; Ried, Thomas; Grade, Marian

doi:10.1002/ijc.28429

Cited by 114 publications

(101 citation statements)

References 51 publications

(123 reference statements)

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“…Similar observations were made very recently in colorectal cancer cell lines in which treatment with Stattic resulted in significant increased sensitivity toward chemoradiotherapy while phosphorylated STAT3 was not detectable. Off-target effects of Stattic in these experiments were excluded by demonstrating identical effects of shRNA-mediated silencing of STAT3 (Spitzner et al, 2014). These puzzling observations in our and this recently published study might be explained by technical issues, for e.g., by the inability to detect low levels of phosphorylated STAT3 that can still have a physiological role.…”

Section: Discussionmentioning

confidence: 67%

Exploring the IL-21–STAT3 Axis as Therapeutic Target for Sézary Syndrome

Fits

Out-Luiting

Tensen

et al. 2014

Journal of Investigative Dermatology

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Sézary syndrome is an aggressive cutaneous T-cell lymphoma. The malignant cells (Sézary cells) are present in skin, lymph nodes, and blood, and express constitutively activated signal transducer and activator of transcription (STAT)3. STAT3 can be activated by IL-21 in vitro and the IL-21 gene itself is a STAT3 target gene, thereby creating an autocrine positive feedback loop that might serve as a therapeutic target. Sézary cells underwent apoptosis when incubated with Stattic, a selective STAT3 inhibitor. STAT3 activation in Sézary cells did not affect expression of the supposed anti-apoptotic STAT3 target genes BCL2, BCL-xL, and SURVIVIN, whereas expression of (proto)oncogenes miR-21, TWIST1, MYC, and PIM1 was significantly increased. CD3/CD28-mediated activation of Sézary cells induced IL-21 expression, accompanied by STAT3 activation and increased proliferation. Blocking IL-21 in CD3/CD28-activated cells had no effects, whereas Stattic abrogated IL-21 expression and cell proliferation. Thus, specific inhibition of STAT3 is highly efficient in the induction of apoptosis of Sézary cells, likely mediated via the regulation of (proto)oncogenes. In contrast, blocking IL-21 alone seems insufficient to affect STAT3 activation, cell proliferation, or apoptosis. These data provide further insights into the pathogenic role of STAT3 in Sézary syndrome and strengthen the notion that STAT3 represents a promising therapeutic target in this disease.

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Section: Discussionmentioning

confidence: 67%

Exploring the IL-21–STAT3 Axis as Therapeutic Target for Sézary Syndrome

Fits

Out-Luiting

Tensen

et al. 2014

Journal of Investigative Dermatology

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“…Conversely inhibition of STAT3 or blockade of G-CSF signaling represents a novel strategy for CSC-specific therapy for neuroblastoma. Previous studies demonstrated the role of STAT3 in IL-6 mediated drug resistance in neuroblastoma (35) and showed STAT3 inhibition sensitizes colorectal cancer and nasopharyngeal carcinoma to both radiation and chemotherapy (36, 37). …”

Section: Discussionmentioning

confidence: 99%

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation

et al. 2015

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Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. We previously isolated a Cancer Stem Cell-like (CSC) subpopulation in neuroblastoma based on differential expression of the receptor for G-CSF (Granulocyte-Colony Stimulating Factor). Here we demonstrate that G-CSF selectively activates signal transducer and activator of transcription 3 (STAT3) within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 transcriptionally activates the G-CSF receptor (encoded by CSF3R), creating a CSC sustaining positive-feedback loop. Blockade of G-CSF/STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depletes the CSC subpopulation within tumors, driving correlated tumor regression, blocking metastasis and increasing chemosensitivity. Taken together, these data define G-CSF as a tumorigenic growth factor for neuroblastoma and suggest a comprehensive re-evaluation of the clinical use of G-CSF in these patients. Our data also demonstrate that direct targeting of the G-CSF/STAT3 signaling represents a novel therapeutic approach for neuroblastoma.

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“…Transfections with synthetic small interfering RNA (siRNA) duplexes were performed as previously described (16,17). Briefly, for cellular viability assays, cells were reverse transfected with siRNAs (Qiagen, Hilden, Germany; Dharmacon/Thermo Fisher Scientific, Schwerte, Germany) using RNAiMAX (Invitrogen) or HiPerFect (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as previously described (9,17). Briefly, 20 μg of whole cell protein lysate was loaded and resolved on an 8% or 10% Bis-Tris polyacrylamide gel.…”

Section: Methodsmentioning

confidence: 99%

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Emons

Spitzner

Reineke

et al. 2017

Molecular Cancer Research

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114

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Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy (CRT) and TCF7L2 mediates resistance to CRT. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small molecule inhibitor (XAV-939) resulted in sensitization of CRC cells to CRT. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand of Frizzled-receptors, which increased resistance to CRT. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to CRT, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy. Implications Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to CRT.

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STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo

Cited by 114 publications

References 51 publications

Exploring the IL-21–STAT3 Axis as Therapeutic Target for Sézary Syndrome

Exploring the IL-21–STAT3 Axis as Therapeutic Target for Sézary Syndrome

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

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