Epidermal Growth Factor Receptor Family Inhibition Identifies P38 Mitogen-activated Protein Kinase as a Potential Therapeutic Target in Bladder Cancer

Vidal, Regina Mora; Mota, Sergio Regufe da; Hayden, Annette; Markham, H. C.; Douglas, James J.; Packham, Graham; Crabb, Simon J.

doi:10.1016/j.urology.2017.10.041

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…HER2 expression in bladder cancer was very heterogeneous throughout different studies and this area is still poorly defined [31]. The notable variability in results between different studies as well as between the cases among each studied group in our results can be eventually explained in the context of genetic level and the newly named molecular classification of the bladder tumors into luminal and basal, as was suggested by Powles et al, 2016 [12].…”

Section: Discussionsupporting

confidence: 55%

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

Esmail¹,

Abdellah²,

Abdel‐Salam³

2020

Open Access Maced J Med Sci

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BACKGROUND: Most of bladder cancers are proven to be of urothelial origin (transitional cell carcinomas). Above 75% of them are of non-muscle invasive bladder cancer (NMIBC) type at presentation and the remainder are MIBC. Recent studies suggest that both are most probably two different categories based on both the histopathological and molecular features. The comprehensive understanding of the biomarkers expression in both categories will help in understanding the molecular event underlying each of them and may provide possible chances for targeted therapeutic options. AIM: This study aims to study the differential expression of both E-cadherin and human epidermal growth factor receptor-2 (HER2) in the two categories of bladder cancer NMIBCs and MIBCs. MATERIALS AND METHODS: A total of 40 blocks were collected retrospectively from cases of cancer bladder, segregated as 20 cases NMIBCs and 20 cases MIBCs, subjected for E-cadherin and HER2 immunostaining. RESULTS: E-cadherin showed positive expression in 65% of cases of NMI group and in 10% of the MI group, with high statistical significance (p < 0.001). Regarding HER2, positive expression was seen in 25% of NMI cases and in 90% of MI cases, with statistical significance (p < 0.001). Comparison of the results of both markers and their correlation per case showed that 90% of tumors with muscle invasion were E-cadherin negative and HER2 positive. CONCLUSION: The significant association of loss of E-cadherin immunohistochemistry expression and positive HER2 overexpression in MIBC versus NMIBC figured out more differences between the two categories and added to the understanding of their biology. The possibility of validation of HER2-targeted therapy in MIBC cases is now strongly suggested.

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Section: Discussionsupporting

confidence: 55%

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

Esmail¹,

Abdellah²,

Abdel‐Salam³

2020

Open Access Maced J Med Sci

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“…Collectively, these results indicate that Src inhibition induced melanogenesis via the p38 MAPK and PKA signaling pathways in G361 cells. These data are also supported by a previous study that indicated that Src inhibition increased p-p38 expression levels (30). Additionally, the suppression of c-Src activity by PP1 and SU6656 stimulated muscle differentiation via p38 MAPK activation (31).…”

Section: Discussionsupporting

confidence: 89%

Src inhibition induces melanogenesis in human G361 cells

Choi

et al. 2019

Mol Med Report

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The Src kinase family (SKF) includes non-receptor tyrosine kinases that interact with many cellular cytosolic, nuclear and membrane proteins, and is involved in the progression of cellular transformation and oncogenic activity. However, there is little to no evidence on the effect of SKF or its inhibitors on melanogenesis. Therefore, the present study investigated whether C-terminal Src kinase inhibition can induce melanogenesis and examined the associated signaling pathways and mRNA expression of melanogenic proteins. First, whether stimulators of melanogenesis, such as ultraviolet B and α-melanocyte-stimulating hormone, can dephosphorylate Src protein was evaluated, and the results revealed that SU6656 and PP2 inhibited the phosphorylation of Src in G361 cells. Src inhibition by these chemical inhibitors induced melanogenesis in G361 cells and upregulated the mRNA expression levels of melanogenesis-associated genes encoding microphthalmia-associated transcription factor, tyrosinase-related protein 1 (TRP1), TRP2, and tyrosinase. In addition, Src inhibition by small interfering RNA induced melanogenesis and upregulated the mRNA expression levels of melanogenesis-associated genes. As the p38 mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element binding (CREB) pathways serve key roles in melanogenesis, the present study further examined whether Src mediates melanogenesis via these pathways. As expected, Src inhibition via SU6656 or PP2 administration induced the phosphorylation of p38 or CREB, as determined by western blotting analysis, and increased the levels of phosphorylated p38 or CREB, as determined by immunofluorescence staining. In addition, the induced pigmentation and melanin content of G361 cells by Src inhibitors was significantly inhibited by p38 or CREB inhibitors. Taken together, these data indicate that Src is associated with melanogenesis, and Src inhibition induces melanogenesis via the MAPK and CREB pathways in G361 cells.

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“…Consistent with previous studies with EGFR1/HER2(ERBB2)-targeted tyrosine kinase inhibitors (TKIs) [34, 40], we found that Lapatinib can cause FOXO3-dephosphorylation (T32) and the downregulation of its target FOXM1 in Lapatinib-sensitive NPC cells. However, although EGFR1/HER2 inhibitors have previously been shown to modulate p38 and JNK activity [41, 42], we did not observe any substantial changes in p38 and JNK phosphorylation/activity in NPC cells in response to Lapatinib treatment, suggesting it is unlikely that Lapatinib modulates FOXO3 activity via p38 and JNK in these NPC cells. FOXM1 is a potent oncogene negatively regulated by FOXO3 [32] and contributes to cancer drug resistance through controlling many genes involved in cell proliferation, survival, DNA repair, and tubulin destabilization [32, 43, 44].…”

Section: Discussioncontrasting

confidence: 81%

Lapatinib sensitivity in nasopharyngeal carcinoma is modulated by SIRT2-mediated FOXO3 deacetylation

et al. 2019

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BackgroundChemoresistance is an obstacle to the successful treatment of nasopharyngeal carcinoma (NPC). Lapatinib is a targeted tyrosine kinase inhibitor therapeutic drug also used to treat NPC, but high doses are often required to achieve a result. To investigate the mechanism for the development of Lapatinib resistance, we characterised a number of NPC cell lines to determine the role of FOXO3 and sirtuins in regulating NPC resistance.MethodsSulforhodamine B (SRB) assays, Clonogenic assays, Protein extraction, quantification and western blotting, RT qPCR, Co-immunoprecipitation assay.ResultsTo explore novel treatment strategies, we first characterized the Lapatinib-sensitivity of a panel of NPC cell lines by SRB and clonogenic cytotoxic assays and found that the metastatic NPC (C666–1 and 5-8F) cells are highly resistant whereas the poorly metastatic lines (6-10B, TW01 and HK-1) are sensitive to Lapatinib. Western blot analysis of the Lapatinib-sensitive 6-10B and resistant 5-8F NPC cells showed that the expression of phosphorylated/inactive FOXO3 (P-FOXO3;T32), its target FOXM1 and its regulator SIRT2 correlate negatively with Lapatinib response and sensitivity, suggesting that SIRT2 mediates FOXO3 deacetylation to promote Lapatinib resistance. In agreement, clonogenic cytotoxic assays using wild-type and foxo1/3/4−/− mouse embryonic fibroblasts (MEFs) showed that FOXO1/3/4-deletion significantly attenuates Lapatinib-induced cytotoxicity, confirming that FOXO proteins are essential for mediating Lapatinib response. SRB cell viability assays using chemical SIRT inhibitors (i.e. sirtinol, Ex527, AGK2 and AK1) revealed that all SIRT inhibitors can reduce NPC cell viability, but only the SIRT2-specific inhibitors AK1 and AGK2 further enhance the Lapatinib cytotoxicity. Consistently, clonogenic assays demonstrated that the SIRT2 inhibitors AK1 and AGK2 as well as SIRT2-knockdown increase Lapatinib cytotoxicity further in both the sensitive and resistant NPC cells. Co-immunoprecipitation studies showed that besides Lapatinib treatment, SIRT2-pharmaceutical inhibition and silencing also led to an increase in FOXO3 acetylation. Importantly, SIRT2 inhibition and depletion further enhanced Lapatinib-mediated FOXO3-acetylation in NPC cells.ConclusionCollectively, our results suggest the involvement of SIRT2-mediated FOXO3 deacetylation in Lapatinib response and sensitivity, and that SIRT2 can specifically antagonise the cytotoxicity of Lapatinib through mediating FOXO3 deacetylation in both sensitive and resistant NPC cells. The present findings also propose that SIRT2 can be an important biomarker for metastatic and Lapatinib resistant NPC and that targeting the SIRT2-FOXO3 axis may provide novel strategies for treating NPC and for overcoming chemoresistance.

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Epidermal Growth Factor Receptor Family Inhibition Identifies P38 Mitogen-activated Protein Kinase as a Potential Therapeutic Target in Bladder Cancer

Abstract: p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow combination therapy strategies to be developed in conjunction with EGFR or HER2 inhibition.

Cited by 15 publications

References 25 publications

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

Src inhibition induces melanogenesis in human G361 cells

Lapatinib sensitivity in nasopharyngeal carcinoma is modulated by SIRT2-mediated FOXO3 deacetylation

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