AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways

Lai, Yi-Hua; Lin, Sih-Yin; Wu, Yu-Shan; Chen, Huei‐Wen; Chen, Jeremy J.W.

doi:10.1186/s13045-017-0539-3

Cited by 14 publications

(11 citation statements)

References 64 publications

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“…The primary antibodies were anti-CXCL8-antibody (60141-2-lg, ProteinTech, 1:1000), anti-DACH1-antibody (10914-1-AP, ProteinTech, 1:1000), and anti-β-actin-antibody ( 60008-1-lg , ProteinTech, 1:2000). Secondary staining and detection were conducted in accordance with standard protocols as previously described [ 30 , 31 ].…”

Section: Methodsmentioning

confidence: 99%

DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis

Liu

et al. 2018

J Hematol Oncol

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BackgroundC-X-C motif ligand 8 (CXCL8), known as a proinflammatory chemokine, exerts multiple effects on the proliferation, invasion, and migration of tumor cells via the autocrine or paracrine manner. Conversely, the human Dachshund homologue 1 (DACH1) is recognized as a tumor suppressor which retards the progression of various cancers. In prostate cancer, it has been demonstrated that DACH1 was negatively correlated with the expression of CXCL8 and able to antagonize the effects of CXCL8 on cellular migration. Herein, we explored the mechanisms by which DACH1 regulated the CXCL8 in non-small cell lung cancer (NSCLC).MethodsPublic microarray and Kaplan-Meier plotter datasets were analyzed. Blood serum samples from lung adenocarcinoma (ADC) patients were collected for enzyme-linked immunosorbent assay (ELISA) analysis. Immunohistochemical staining was conducted on tissue microarray. Cell lines with stable expression of DACH1 were established, and relative gene expression was measured by Western blot, ELISA, real-time PCR, and human cytokine array. Correspondingly, cell lines transfected with shDACH1 were established, and relative gene expression was measured by real-time PCR and immunofluorescence array. Functional studies were performed by transwell and xenograft mice models. Luciferase reporter gene assay was applied to measure the regulation of DACH1 on CXCL8.ResultsOur study indicated that CXCL8 both at the mRNA and protein level was associated with the high tumor burden of ADC. Correlational analyses in ADC cell lines and ADC tissues showed that DACH1 was inversely correlated with CXCL8. Meanwhile, patients with high DACH1 expression and low CXCL8 expression had prolonged time to death and recurrence. Moreover, we verified the inhibitory effects of DACH1 on CXCL8 both in vitro and in vivo. Mechanism studies proved that DACH1 transcriptionally repressed CXCL8 promoter activity through activator protein-1 (AP-1) and nuclear transcription factor-kappa B (NF-κB) sites.ConclusionsOur study proved that CXCL8 acted as an unfavorable factor promoting to tumor progression and poor prognosis of ADC, while DACH1 antagonized CXCL8 to provide a favorable survival of ADC patients. Double detection of DACH1 and CXCL8 may provide a precise information for further evaluating the prognosis of ADC patients.

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Section: Methodsmentioning

confidence: 99%

DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis

Liu

et al. 2018

J Hematol Oncol

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“…EGFR inhibitors, like gefitinib and erlotinib, were found in non-small cell lung cancer (NSCLC) to reduce activation of Src and its substrates, suggesting the prominent role of Src in NSCLC progression. Indeed, some authors showed how, in combination with established therapeutic agents, AC-93253 iodide, a Src-EGFR crosstalk inhibitor, blocked cancer cell growth and motility [73]. In EGFR mutated NSCLC, EMT has been associated with acquired resistance to the EGFR inhibitor erlotinib.…”

Section: Lung Cancermentioning

confidence: 99%

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

Martellucci

Clementi

Sabetta

et al. 2020

Cancers

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Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression

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“…Using in vitro melanoma cell line-based screening, we previously identified an inhibitor of SIRT2, AC-93253, as a compound that downregulates the expression of genes involved in melanoma progression and chemoresistance acquisition [49]. This compound was subsequently also identified as an SRC inhibitor [51]. These findings prompted us to perform a more detailed analysis of the role of SIRT2 in melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib

Karwaciak

Sałkowska

Karaś

et al. 2019

Cancers

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Malignant melanoma is the most aggressive skin cancer and can only be cured if detected early. Unfortunately, later stages of the disease do not guarantee success due to the rapid rate of melanoma cell metastasis and their high resistance to applied therapies. The search for new molecular targets and targeted therapy may represent the future in the development of effective methods for combating this cancer. SIRT2 is a promising target; thus, we downregulated SIRT2 expression in melanoma cells in vertical growth and metastatic phases and demonstrated that sirtuin acts as regulator of the basic functions of melanoma cells. A detailed transcriptomic analysis showed that SIRT2 regulates the expression of multiple genes encoding the tyrosine kinase pathways that are molecular targets of dasatinib. Indeed, cells with low SIRT2 expression were more susceptible to dasatinib, as demonstrated by multiple techniques, e.g., neutral red uptake, 3/7 caspase activity, colony formation assay, and in vitro scratch assay. Furthermore, these cells showed an altered phosphorylation profile for proteins playing roles in the response to dasatinib. Thus, our research indicates new, previously unknown SIRT2 functions in the regulation of gene expression, which is of key clinical significance.

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AC-93253 iodide, a novel Src inhibitor, suppresses NSCLC progression by modulating multiple Src-related signaling pathways

Cited by 14 publications

References 64 publications

DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis

DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis

Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far

SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib

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