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Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody.

Zhuang HQ, Zhuang H, Bo Q, Guo Y, Wang J, Zhao LJ, Yuan ZY, Wang P - Cancer Cell Int. (2014)

Bottom Line: The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib.The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China ; Tianjin Lung Cancer Center, Tianjin, China.

ABSTRACT

Purpose: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization.

Methods: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis.

Results: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.

Conclusions: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

No MeSH data available.


Related in: MedlinePlus

Protein expression in colony-forming cells from the combined erlotinib and radiation group before and after c-MET inhibition. The radiation dose was 6Gy. Erlotinib was used at a concentration of 20 nM. The anti-c-MET monoclonal antibody was applied at a concentration of 10 nM too. (A) Control group. (B) Combined erlotinib and radiation group. (C) Combined erlotinib and radiation with anti-c-MET monoclonal antibody treatment group.
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Fig4: Protein expression in colony-forming cells from the combined erlotinib and radiation group before and after c-MET inhibition. The radiation dose was 6Gy. Erlotinib was used at a concentration of 20 nM. The anti-c-MET monoclonal antibody was applied at a concentration of 10 nM too. (A) Control group. (B) Combined erlotinib and radiation group. (C) Combined erlotinib and radiation with anti-c-MET monoclonal antibody treatment group.

Mentions: To study the possible survival mechanism utilized by colony-forming cells, cells from the blank control group, the combined erlotinib and radiation group, and the combined erlotinib and radiation with anti-c-MET monoclonal antibody group were collected after 14 days of treatment, and the expression of c-MET, phosphorylated c-MET, PI3K, AKT, and phosphorylated AKT was examined. The results showed that the expression of these proteins significantly increased after 14 days of treatment. However, after treatment with the anti-c-MET monoclonal antibody, the expression of these proteins significantly decreased (Figure 4). Moreover, the changes in protein expression observed before and after inhibiting the c-MET-PI3K-AKT pathway using the anti-c-MET monoclonal antibody further indicated that the activation of the c-MET-PI3K-AKT pathway was an important mechanism for A973 cell survival and colony formation after the combined treatment with erlotinib and radiation. Therefore, blockade of this pathway may represent a novel approach for enhancing the radiosensitizing effect of erlotinib.Figure 4


Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody.

Zhuang HQ, Zhuang H, Bo Q, Guo Y, Wang J, Zhao LJ, Yuan ZY, Wang P - Cancer Cell Int. (2014)

Protein expression in colony-forming cells from the combined erlotinib and radiation group before and after c-MET inhibition. The radiation dose was 6Gy. Erlotinib was used at a concentration of 20 nM. The anti-c-MET monoclonal antibody was applied at a concentration of 10 nM too. (A) Control group. (B) Combined erlotinib and radiation group. (C) Combined erlotinib and radiation with anti-c-MET monoclonal antibody treatment group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4263203&req=5

Fig4: Protein expression in colony-forming cells from the combined erlotinib and radiation group before and after c-MET inhibition. The radiation dose was 6Gy. Erlotinib was used at a concentration of 20 nM. The anti-c-MET monoclonal antibody was applied at a concentration of 10 nM too. (A) Control group. (B) Combined erlotinib and radiation group. (C) Combined erlotinib and radiation with anti-c-MET monoclonal antibody treatment group.
Mentions: To study the possible survival mechanism utilized by colony-forming cells, cells from the blank control group, the combined erlotinib and radiation group, and the combined erlotinib and radiation with anti-c-MET monoclonal antibody group were collected after 14 days of treatment, and the expression of c-MET, phosphorylated c-MET, PI3K, AKT, and phosphorylated AKT was examined. The results showed that the expression of these proteins significantly increased after 14 days of treatment. However, after treatment with the anti-c-MET monoclonal antibody, the expression of these proteins significantly decreased (Figure 4). Moreover, the changes in protein expression observed before and after inhibiting the c-MET-PI3K-AKT pathway using the anti-c-MET monoclonal antibody further indicated that the activation of the c-MET-PI3K-AKT pathway was an important mechanism for A973 cell survival and colony formation after the combined treatment with erlotinib and radiation. Therefore, blockade of this pathway may represent a novel approach for enhancing the radiosensitizing effect of erlotinib.Figure 4

Bottom Line: The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib.The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China ; Tianjin Lung Cancer Center, Tianjin, China.

ABSTRACT

Purpose: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization.

Methods: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis.

Results: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.

Conclusions: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

No MeSH data available.


Related in: MedlinePlus