Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation

Chen, Bo; Liang, Yan; He, Zheng; An, Yunhe; Zhao, Weihong; Wu, Jianzhong

doi:10.1038/srep30404

Cited by 47 publications

(43 citation statements)

References 27 publications

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“…To elucidate mechanisms by which STAT3 inhibition might enhance the sensitivity of NB cells to cisplatin, we evaluated the DNA damage response pathway by Western analysis. In response to DNA damage, ATM and ATR are activated leading to activation of H2AX as well as their respective downstream targets Chk2 and Chk1 (33, 34). Activation of both the ATM and ATR DNA damage response pathways are detected after cisplatin treatment as indicated by the increases in phosphorylation of their respective downstream targets.…”

Section: Resultsmentioning

confidence: 99%

“…In NB cells, high-level expression of wild-type ALK in cells constitutively expressing putative ALK ligands (31) or mutations in ALK (32) contribute to levels of P-STAT3. Although not systematically studied, growth factors known to be produced by NB cells, such as IGF-1 (33), BDNF (34, our unpublished data) stimulate increases in P-STAT3. These factors as well as growth factors contained in serum may contribute to the levels of P-STAT3 detected in NB cells cultured in vitro .…”

Section: Discussionmentioning

confidence: 95%

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Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity

Odate

Veschi

Yan

et al. 2017

Clinical Cancer Research

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Purpose Neuroblastoma (NB) is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk NB is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk NB. Experimental Design To evaluate the biologic consequences of specific targeting of STAT3 in NB, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in 3 representative NB cell line models (AS, NGP and IMR32). Results Our data indicated that Tet-inducible STAT3 shRNA and AZD9150 inhibited endogenous STAT3 and STAT3 target genes. Tet-inducible STAT3 shRNA and AZD9150 decreased cell growth and tumorigenicity. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA or AZD9150 alone had little effect on growth of established tumors. However, when treated xenograft tumor cells were re-implanted into mice there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared to the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of NB cells. Furthermore, inhibition of STAT3 significantly increased NB cell sensitivity to cisplatin and decreased tumor growth and increased the survival of tumor-bearing mice in vivo. Conclusion Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk NB.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity

Odate

Veschi

Yan

et al. 2017

Clinical Cancer Research

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“…25 Recently, there has some evidence confirmed that BDNF and/or its receptor TrkB play roles in several cancers, including gastric cancer, 26 cervical cancer, 27 and glioma. 25 Recently, there has some evidence confirmed that BDNF and/or its receptor TrkB play roles in several cancers, including gastric cancer, 26 cervical cancer, 27 and glioma.…”

Section: Discussionmentioning

confidence: 99%

P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway

Huo

Chen

2018

J of Cellular Biochemistry

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Purinergic receptor P2X 4 (P2X4R), a member of purinergic channels family and a subtype of ionotropic adenosine triphosphate receptors, plays a critical role in tumorigenesis. Evidence suggested that P2X4R is expressed in rat C6 glioma model, however, its role and the underlying mechanism of action are still unclear in human glioblastoma multiforme (GBM). In the current study, our aim is to examine the function and the molecular basis of P2X4R in GBM. We first observed that GBM cells, U251, T98, U87, U373, and A172 were all high expressed P2X4R, when compared with the normal human astrocytes (NHA) cells. To gain the function of P2X4R, P2X4R silence cells were constructed by transfection with P2X4R small interfering RNA (siRNA). We found that P2X4R deletion impeded T98 and U87 cell viability and proliferation, and further studies indicated that cell apoptosis and caspase‐3 activity was increased in T98 and U87 cell transfected with P2X4R siRNA. Subsequently, we confirmed that P2X4R silence suppressed brain‐derived neurotrophic factor (BDNF), Trk receptor tyrosine kinases (TrkB), and activating transcription factor 4 (ATF4) expression in T98 and U87 cells. And P2X4R siRNA–induced ATF4‐expression inhibition dependent on BDNF/TrkB signaling pathway. The impact of P2X4R silence on T98 and U87 cell growth and apoptosis was reversed by ATF4 overexpression. In summary, this study provides the first evidence that P2X4R plays important roles in GBM cell growth and apoptosis.

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“…Moreover, BDNF has been shown to promote non-small lung cancer proliferation in an autocrine manner and metastasis of neuroblastoma through STAT3 and PI3K and MAPKsingalling pathway, respectively [21, 31]. …”

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer

et al. 2017

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AimsThere is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells.MethodsWe conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples.ResultsThe results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for △BDNF and △TrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS.ConclusionOur study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients.

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Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation

Cited by 47 publications

References 27 publications

Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity

Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity

P2X4R silence suppresses glioma cell growth through BDNF/TrkB/ATF4 signaling pathway

Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer

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