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Radiation promotes malignant phenotypes through SRC in breast cancer cells.

Kim RK, Cui YH, Yoo KC, Kim IG, Lee M, Choi YH, Suh Y, Lee SJ - Cancer Sci. (2014)

Bottom Line: However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure.Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3-kinase/protein kinase B and p38 MAPK signaling.In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.

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Radiation-activated SRC transduces intracellular signaling of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and p38 MAPK to increase migratory and invasive behavior. (a) PI3 kinase assay and Western blot analysis for phosphorylation status of AKT and p38 MAPK in MCF7 cancer cells transfected with siRNA targeting SRC or scrambled control siRNA (si-Cont) prior to irradiation. (b) Western blot analysis for phosphorylation status of AKT in MCF7 cancer cells transfected by dominant negative (DN)-p38 or control pCMV5 prior to irradiation. (c) Migration and invasion assay in MCF7 breast cancer cells transfected with siRNA targeting AKT (si-AKT) or scrambled control siRNA prior to irradiation. β-actin was used as a loading control. Error bars represent mean ± SD of triplicate samples. **P < 0.01. PTEN, phosphatase and tensin homolog. Cont, control.
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fig03: Radiation-activated SRC transduces intracellular signaling of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and p38 MAPK to increase migratory and invasive behavior. (a) PI3 kinase assay and Western blot analysis for phosphorylation status of AKT and p38 MAPK in MCF7 cancer cells transfected with siRNA targeting SRC or scrambled control siRNA (si-Cont) prior to irradiation. (b) Western blot analysis for phosphorylation status of AKT in MCF7 cancer cells transfected by dominant negative (DN)-p38 or control pCMV5 prior to irradiation. (c) Migration and invasion assay in MCF7 breast cancer cells transfected with siRNA targeting AKT (si-AKT) or scrambled control siRNA prior to irradiation. β-actin was used as a loading control. Error bars represent mean ± SD of triplicate samples. **P < 0.01. PTEN, phosphatase and tensin homolog. Cont, control.

Mentions: In the above data, we showed that irradiation induces activation of SRC, thereby increasing SLUG expression and triggering EMT in breast cancer cells. Thus, we examined the intracellular signaling pathways that are triggered by SRC and are responsible for radiation-induced EMT in breast cancer cells. Importantly, we found that PI3K/AKT and p38 signaling pathways are activated by irradiation; however, treatment with siRNA targeting SRC attenuated the radiation-induced activation of PI3K/AKT and p38 (Fig.3a). We next examined the phosphorylation status of AKT after transfection with the DN mutant form of p38. Of note, transfection with DN-p38 effectively inhibited the phosphorylation of AKT on Ser473, whereas DN-p38 had no effect on the phosphorylation of Thr308, suggesting that p38 is a downstream effector of SRC, promoting phosphorylation of AKT on Ser473 (Fig.3b). Also, transfection with DN-p38 attenuated radiation-induced EMT markers such as N-cadherin and vimentin, and EMT transcription factor SLUG (Fig. S2b). In line with these results, treatment with siRNA targeting AKT effectively mitigated the radiation-induced migratory and invasive properties of MCF7 breast cancer cells (Fig.3c). In agreement, treatment with PI3K specific inhibitor LY294002 attenuated radiation-induced EMT markers and regulator SLUG (Fig. S2c). Taken together, these results suggest that radiation promotes the EMT program by SRC-mediated activation of PI3K and p38 MAPK that consequently activates AKT signaling in breast cancer cells.


Radiation promotes malignant phenotypes through SRC in breast cancer cells.

Kim RK, Cui YH, Yoo KC, Kim IG, Lee M, Choi YH, Suh Y, Lee SJ - Cancer Sci. (2014)

Radiation-activated SRC transduces intracellular signaling of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and p38 MAPK to increase migratory and invasive behavior. (a) PI3 kinase assay and Western blot analysis for phosphorylation status of AKT and p38 MAPK in MCF7 cancer cells transfected with siRNA targeting SRC or scrambled control siRNA (si-Cont) prior to irradiation. (b) Western blot analysis for phosphorylation status of AKT in MCF7 cancer cells transfected by dominant negative (DN)-p38 or control pCMV5 prior to irradiation. (c) Migration and invasion assay in MCF7 breast cancer cells transfected with siRNA targeting AKT (si-AKT) or scrambled control siRNA prior to irradiation. β-actin was used as a loading control. Error bars represent mean ± SD of triplicate samples. **P < 0.01. PTEN, phosphatase and tensin homolog. Cont, control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317785&req=5

fig03: Radiation-activated SRC transduces intracellular signaling of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and p38 MAPK to increase migratory and invasive behavior. (a) PI3 kinase assay and Western blot analysis for phosphorylation status of AKT and p38 MAPK in MCF7 cancer cells transfected with siRNA targeting SRC or scrambled control siRNA (si-Cont) prior to irradiation. (b) Western blot analysis for phosphorylation status of AKT in MCF7 cancer cells transfected by dominant negative (DN)-p38 or control pCMV5 prior to irradiation. (c) Migration and invasion assay in MCF7 breast cancer cells transfected with siRNA targeting AKT (si-AKT) or scrambled control siRNA prior to irradiation. β-actin was used as a loading control. Error bars represent mean ± SD of triplicate samples. **P < 0.01. PTEN, phosphatase and tensin homolog. Cont, control.
Mentions: In the above data, we showed that irradiation induces activation of SRC, thereby increasing SLUG expression and triggering EMT in breast cancer cells. Thus, we examined the intracellular signaling pathways that are triggered by SRC and are responsible for radiation-induced EMT in breast cancer cells. Importantly, we found that PI3K/AKT and p38 signaling pathways are activated by irradiation; however, treatment with siRNA targeting SRC attenuated the radiation-induced activation of PI3K/AKT and p38 (Fig.3a). We next examined the phosphorylation status of AKT after transfection with the DN mutant form of p38. Of note, transfection with DN-p38 effectively inhibited the phosphorylation of AKT on Ser473, whereas DN-p38 had no effect on the phosphorylation of Thr308, suggesting that p38 is a downstream effector of SRC, promoting phosphorylation of AKT on Ser473 (Fig.3b). Also, transfection with DN-p38 attenuated radiation-induced EMT markers such as N-cadherin and vimentin, and EMT transcription factor SLUG (Fig. S2b). In line with these results, treatment with siRNA targeting AKT effectively mitigated the radiation-induced migratory and invasive properties of MCF7 breast cancer cells (Fig.3c). In agreement, treatment with PI3K specific inhibitor LY294002 attenuated radiation-induced EMT markers and regulator SLUG (Fig. S2c). Taken together, these results suggest that radiation promotes the EMT program by SRC-mediated activation of PI3K and p38 MAPK that consequently activates AKT signaling in breast cancer cells.

Bottom Line: However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure.Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3-kinase/protein kinase B and p38 MAPK signaling.In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.

Show MeSH
Related in: MedlinePlus