Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

Ji, Xiang; He, Ming

doi:10.18632/aging.102193

Cited by 24 publications

(16 citation statements)

References 54 publications

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“…4A ). Abnormal activation of STAT3 in tumor cells ensures the survival of malignant cells under stress conditions and also leads to multi-drug resistance ( 24 ). Erlotinib did not reduce the higher levels of STAT3 phosphorylation in HCC827ER cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

et al. 2020

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Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used in the treatment of non-small cell lung cancer (NSCLC). However, erlotinib resistance leads to high mortality in patients with NSCLC, while the activation of STAT3 is closely related to erlotinib resistance. Studies have shown that the main components of Huanglian Jiedu Decoction (HJD) have antitumor effects. Therefore, the anticancer effect of HJD combined with erlotinib on NSCLC cells was investigated. The NSCLC HCC827, HCC827ER, and H1975 cell lines as well as xenograft nude mice were selected as models to study the effects of HJD. The proapoptotic effects of HJD were examined by CCK-8 and apoptosis assays. ELISA, immunostaining, and western blot analysis were also performed. HJD considerably enhanced the anticancer effect of erlotinib in both EGFR-TKI-resistant and -sensitive NSCLC cells. HJD promoted erlotinib-induced apoptosis and caspase 3 activity. The co-treatment also inhibited the expression of Bcl-XL, Bcl-2, and p-STAT3. In addition, siSTAT3 had similar functions with HJD. In particular, the apoptotic rates of erlotinib-stimulated HCC827, HCC827ER, and H1975 cells were enhanced by transfecting siSTAT3. Furthermore, overexpression of STAT3 significantly inhibited HJD-mediated erlotinib sensitization. The combined use of HJD with erlotinib significantly reduced tumor growth in erlotinib-resistant HCC827ER and H1975 ×enografts, induced caspase 3, and inhibited Ki67, STAT3, and Bcl-2 expression. HJD significantly alleviated erlotinib resistance by regulating the STAT3/Bcl-2 signaling pathway, which is a promising method to overcome the EGFR-TKI resistance of NSCLC.

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Section: Resultsmentioning

confidence: 99%

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

et al. 2020

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“…However, a number of studies showed that OS cells had resistance to EGFR inhibitors and the resistance could be overcome by combination with other treatment. Ji et al demonstrated that combined EGFR/STAT3 inhibition could overcome resistance of EGFR inhibition [ 45 ]. In another study, Gvozdenovic et al found that co-targeting of IGF-IR and EGFR signaling was a useful therapeutic strategy to overcome resistance EGFR inhibitors in OS [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma

Yang

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Osteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown. Methods We investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS. Results Myosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo. Conclusion Our results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients.

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“…Abnormal expression of AMBRA1 is associated with prognosis of bile duct cancer and cutaneous melanoma [58,59]. Xiang et al [60] showed that abnormal expression of EGFR is related to drug resistance in tumor patients. Chu et al [61] showed that PEX3 is related to the invasion and metastasis of ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel autophagy-related gene signature for predicting metastasis and survival in patients with osteosarcoma

Zhang

Deng

et al. 2020

Preprint

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Background: Osteosarcoma (OS) is a bone malignant tumor that occurs in children and adolescents. Due to a lack of reliable prognostic biomarkers, the prognosis of OS patients is often uncertain. This study aimed to construct an autophagy-related gene signature to predict the prognosis of OS patients.Methods: The gene expression profile data of OS and normal muscle tissue samples were downloaded separately from the Therapeutically Applied Research To Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) databases . The differentially expressed autophagy-related genes (DEARGs) in OS and normal muscle tissue samples were screened using R software, before being subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A protein-protein interaction (PPI) network was constructed and hub autophagy-related genes were screened. Finally, the screened autophagy-related genes were subjected to univariate Cox regression, Lasso Cox regression, survival analysis, and clinical correlation analysis.Results: A total of 120 DEARGs and 10 hub autophagy-related genes were obtained. A prognostic autophagy-related gene signature consisting of 9 genes ( BNIP3 , MYC , BAG1 , CALCOCO2 , ATF4 , AMBRA1 , EGFR , MAPK1 , and PEX ) was constructed. This signature was significantly correlated to the prognosis ( P <0.0001) and distant metastasis of OS patients ( P = 0.013).Conclusion: This signature based on 9 autophagy-related genes could predict metastasis and survival in patients with OS.

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Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

Cited by 24 publications

References 54 publications

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR‑mutated NSCLC cells in vitro and in vivo via STAT3/Bcl‑2 signaling

MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma

Identification of a novel autophagy-related gene signature for predicting metastasis and survival in patients with osteosarcoma

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