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MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer.

Sun L, Liu L, Liu X, Wang Y, Li M, Yao L, Yang J, Ji G, Guo C, Pan Y, Liang S, Wang B, Ding J, Zhang H, Shi Y - Cancer Sci. (2014)

Bottom Line: However, the MGr1-Ag-initiated intracellular signal transduction pathway is still unknown.Further study found that, as a receptor of ECM components, MGr1-Ag/37LRP may activate the downstream signal pathway PI3K/AKT and MAPK/ERK through interaction with phosphorylated FAK.Moreover, the sensitivity to chemotherapeutic drugs could be significantly enhanced by inhibiting MGr1-Ag/37LRP expression through mAbs, siRNA, and antisense oligonucleotide.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

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Effect of AKT and ERK1/2 activated by phosphorylated focal adhesion kinase (pFAK) on laminin (LN)- and exogenous MGr1-Ag/37LRP induced upregulation of Bcl-2. (a) Effect of exogenous MGr1-Ag/37LRP on AKT and ERK1/2 activation in gastric cancer (GC) cells that expressed up- or downregulated MGr1-Ag/37LRP. (b) Effect of adhesion to LN on AKT and ERK1/2 activation in GC cells. SGC7901 cells were cultured in 6-well plates coated by LN substrate (1 μg/cm2) or BSA as control for 4 h, followed by various doses of U0126 and LY294002 for 1 h. (c, d) SGC7901 cells were cultured in serum-free medium overnight, followed by transiently transfected MGr1-Ag or FAK siRNA expression plasmid (scramble sequence as control). The treated cells were then transferred into 6-well plates of LN substrate (1 μg/cm2) for 4 h. Cell lysates were subjected to Western blot analysis using antibodies against MGr1-Ag pFAK, total FAK, pAKT, total AKT (tAKT), pERK1/2, tERK1/2, Bcl-2, and β-actin. Representative experiments are shown from three for each cell type.
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fig03: Effect of AKT and ERK1/2 activated by phosphorylated focal adhesion kinase (pFAK) on laminin (LN)- and exogenous MGr1-Ag/37LRP induced upregulation of Bcl-2. (a) Effect of exogenous MGr1-Ag/37LRP on AKT and ERK1/2 activation in gastric cancer (GC) cells that expressed up- or downregulated MGr1-Ag/37LRP. (b) Effect of adhesion to LN on AKT and ERK1/2 activation in GC cells. SGC7901 cells were cultured in 6-well plates coated by LN substrate (1 μg/cm2) or BSA as control for 4 h, followed by various doses of U0126 and LY294002 for 1 h. (c, d) SGC7901 cells were cultured in serum-free medium overnight, followed by transiently transfected MGr1-Ag or FAK siRNA expression plasmid (scramble sequence as control). The treated cells were then transferred into 6-well plates of LN substrate (1 μg/cm2) for 4 h. Cell lysates were subjected to Western blot analysis using antibodies against MGr1-Ag pFAK, total FAK, pAKT, total AKT (tAKT), pERK1/2, tERK1/2, Bcl-2, and β-actin. Representative experiments are shown from three for each cell type.

Mentions: We found that LN- and exogenous MGr1-Ag/37LRP could induce phosphorylation of FAK in GC cells. As the survival pathways of PI3K/AKT and MEK/ERK1/2 could be activated by pFAK. We previously reported that MGr1-Ag overexpression could increase expression of Bcl-2 protein. So, we examined whether LN and exogenous MGr1-Ag/37LRP induced the upregulation of Bcl-2 through activation of the PI3K/AKT and MEK/ERK1/2 signaling pathways by Western blot analysis. As shown in Figure3, exogenous MGr1-Ag/37LRP and LN substrate could greatly increase AKT and ERK1/2 phosphorylation in SGC7901 cells. Transient transfection of cells with MGr1-Ag/37LRP or FAK siRNA partly blocked LN-induced AKT and ERK1/2 phosphorylation and inhibited LN-induced Bcl-2 expression. In addition, treatment with PI3K-specific inhibitor LY294002 and MEK1/2-specific inhibitor U0126 could block LN-induced AKT and ERK1/2 phosphorylation, respectively, and inhibited LN-induced Bcl-2 expression. It was concluded that LN- and exogenous MGr1-Ag/37LRP induced Bcl-2 expression may partly through signal pathway FAK-PI3K/Akt and MEK/ERK1/2.


MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer.

Sun L, Liu L, Liu X, Wang Y, Li M, Yao L, Yang J, Ji G, Guo C, Pan Y, Liang S, Wang B, Ding J, Zhang H, Shi Y - Cancer Sci. (2014)

Effect of AKT and ERK1/2 activated by phosphorylated focal adhesion kinase (pFAK) on laminin (LN)- and exogenous MGr1-Ag/37LRP induced upregulation of Bcl-2. (a) Effect of exogenous MGr1-Ag/37LRP on AKT and ERK1/2 activation in gastric cancer (GC) cells that expressed up- or downregulated MGr1-Ag/37LRP. (b) Effect of adhesion to LN on AKT and ERK1/2 activation in GC cells. SGC7901 cells were cultured in 6-well plates coated by LN substrate (1 μg/cm2) or BSA as control for 4 h, followed by various doses of U0126 and LY294002 for 1 h. (c, d) SGC7901 cells were cultured in serum-free medium overnight, followed by transiently transfected MGr1-Ag or FAK siRNA expression plasmid (scramble sequence as control). The treated cells were then transferred into 6-well plates of LN substrate (1 μg/cm2) for 4 h. Cell lysates were subjected to Western blot analysis using antibodies against MGr1-Ag pFAK, total FAK, pAKT, total AKT (tAKT), pERK1/2, tERK1/2, Bcl-2, and β-actin. Representative experiments are shown from three for each cell type.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317895&req=5

fig03: Effect of AKT and ERK1/2 activated by phosphorylated focal adhesion kinase (pFAK) on laminin (LN)- and exogenous MGr1-Ag/37LRP induced upregulation of Bcl-2. (a) Effect of exogenous MGr1-Ag/37LRP on AKT and ERK1/2 activation in gastric cancer (GC) cells that expressed up- or downregulated MGr1-Ag/37LRP. (b) Effect of adhesion to LN on AKT and ERK1/2 activation in GC cells. SGC7901 cells were cultured in 6-well plates coated by LN substrate (1 μg/cm2) or BSA as control for 4 h, followed by various doses of U0126 and LY294002 for 1 h. (c, d) SGC7901 cells were cultured in serum-free medium overnight, followed by transiently transfected MGr1-Ag or FAK siRNA expression plasmid (scramble sequence as control). The treated cells were then transferred into 6-well plates of LN substrate (1 μg/cm2) for 4 h. Cell lysates were subjected to Western blot analysis using antibodies against MGr1-Ag pFAK, total FAK, pAKT, total AKT (tAKT), pERK1/2, tERK1/2, Bcl-2, and β-actin. Representative experiments are shown from three for each cell type.
Mentions: We found that LN- and exogenous MGr1-Ag/37LRP could induce phosphorylation of FAK in GC cells. As the survival pathways of PI3K/AKT and MEK/ERK1/2 could be activated by pFAK. We previously reported that MGr1-Ag overexpression could increase expression of Bcl-2 protein. So, we examined whether LN and exogenous MGr1-Ag/37LRP induced the upregulation of Bcl-2 through activation of the PI3K/AKT and MEK/ERK1/2 signaling pathways by Western blot analysis. As shown in Figure3, exogenous MGr1-Ag/37LRP and LN substrate could greatly increase AKT and ERK1/2 phosphorylation in SGC7901 cells. Transient transfection of cells with MGr1-Ag/37LRP or FAK siRNA partly blocked LN-induced AKT and ERK1/2 phosphorylation and inhibited LN-induced Bcl-2 expression. In addition, treatment with PI3K-specific inhibitor LY294002 and MEK1/2-specific inhibitor U0126 could block LN-induced AKT and ERK1/2 phosphorylation, respectively, and inhibited LN-induced Bcl-2 expression. It was concluded that LN- and exogenous MGr1-Ag/37LRP induced Bcl-2 expression may partly through signal pathway FAK-PI3K/Akt and MEK/ERK1/2.

Bottom Line: However, the MGr1-Ag-initiated intracellular signal transduction pathway is still unknown.Further study found that, as a receptor of ECM components, MGr1-Ag/37LRP may activate the downstream signal pathway PI3K/AKT and MAPK/ERK through interaction with phosphorylated FAK.Moreover, the sensitivity to chemotherapeutic drugs could be significantly enhanced by inhibiting MGr1-Ag/37LRP expression through mAbs, siRNA, and antisense oligonucleotide.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Show MeSH
Related in: MedlinePlus