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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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Related in: MedlinePlus

Effect of MGr1-Ag/37LRP mAb, siRNA, and antisense oligonucleotide (ASO) treatment on SGC7901/VCR tumor growth and chemosensitivity in vivo. (A) Mice bearing SGC7901/VCR tumors were randomly selected for treatment with vincristine (VCR) plus mAb (VAb), VCR plus siRNA (VSM), VCR plus ASO (VAS), VCR alone (VCR), VCR plus scrambled siRNA (VSP), VCR plus scrambled ASO (VNS), VCR plus control antibody (VIg), or the untreated group (TB). When SGC7901/VCR tumors reached 200 mm3, 0.2 mg/kg siRNA or scrambled siRNA, 100 mg/kg antibody MGr1 or control antibody, 10 mg/kg ASO or scrambled ASO were injected once every 3 days for 36 days. From days 7–14 and 21–28, 0.6 mg/kg VCR was given weekly by tail vein injection. Tumor volume was measured every 4 days and calculated by the formula: length × width × depth × 0.5236. Each point represents the mean tumor volume in each experimental group containing 10 mice. *P > 0.05 in each control group; #P < 0.05 versus respective controls, by least significant difference t-test. (B) Protein expression of MGr1-Ag/37LRP, phosphorylated focal adhesion kinase (pFAK), total FAK (tFAK), pAKT, tAKT, and Bcl-2 in vivo. Lysates were resolved by SDS-PAGE, and MGr1-Ag/37LRP, pFAK, tFAK, pAKT, tAKT, pERK, and tERK, Bcl-2 or β-actin (as indicated) was assessed by Western blot analysis. Representative experiments are shown from three for each cell type. (C) Immunohistochemical staining for MGr1-Ag/37LRP of paraffin-embedded sections from s.c. tumors: (a) negative control group; (b) TB group; (c) VCR group; (d) VAb group; (e) VSM group; (f) VAS group; (g) VIg group; (h) VSP group; (i) VNS group (original magnification, 200×). The results shown are representative of three independent experiments.
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fig05: Effect of MGr1-Ag/37LRP mAb, siRNA, and antisense oligonucleotide (ASO) treatment on SGC7901/VCR tumor growth and chemosensitivity in vivo. (A) Mice bearing SGC7901/VCR tumors were randomly selected for treatment with vincristine (VCR) plus mAb (VAb), VCR plus siRNA (VSM), VCR plus ASO (VAS), VCR alone (VCR), VCR plus scrambled siRNA (VSP), VCR plus scrambled ASO (VNS), VCR plus control antibody (VIg), or the untreated group (TB). When SGC7901/VCR tumors reached 200 mm3, 0.2 mg/kg siRNA or scrambled siRNA, 100 mg/kg antibody MGr1 or control antibody, 10 mg/kg ASO or scrambled ASO were injected once every 3 days for 36 days. From days 7–14 and 21–28, 0.6 mg/kg VCR was given weekly by tail vein injection. Tumor volume was measured every 4 days and calculated by the formula: length × width × depth × 0.5236. Each point represents the mean tumor volume in each experimental group containing 10 mice. *P > 0.05 in each control group; #P < 0.05 versus respective controls, by least significant difference t-test. (B) Protein expression of MGr1-Ag/37LRP, phosphorylated focal adhesion kinase (pFAK), total FAK (tFAK), pAKT, tAKT, and Bcl-2 in vivo. Lysates were resolved by SDS-PAGE, and MGr1-Ag/37LRP, pFAK, tFAK, pAKT, tAKT, pERK, and tERK, Bcl-2 or β-actin (as indicated) was assessed by Western blot analysis. Representative experiments are shown from three for each cell type. (C) Immunohistochemical staining for MGr1-Ag/37LRP of paraffin-embedded sections from s.c. tumors: (a) negative control group; (b) TB group; (c) VCR group; (d) VAb group; (e) VSM group; (f) VAS group; (g) VIg group; (h) VSP group; (i) VNS group (original magnification, 200×). The results shown are representative of three independent experiments.

Mentions: We then evaluated the effects of MGr1-Ag/37LRP mAb, siRNA, and ASO treatment on the chemotherapy of SGC7901/VCR tumors in vivo. Figure5(A) shows that therapy groups VCR plus mAb, VCR plus siRNA, and VCR plus ASO significantly reduced SGC7901/VCR tumor volume by 50% from days 16 to 40 compared to treatment with VCR alone, VCR plus control antibody, VCR plus scrambled siRNA, and VCR plus scrambled ASO, and the untreated group. In addition, after first treatment with VCR, from days 12 to 20, monotherapy of VCR significantly reduced SGC7901/VCR tumor volume compared to the untreated group. However, after first treatment with VCR, from days 24 to 40, there was no difference in SGC7901/VCR tumor volume between the VCR monotherapy group and the untreated group. Immunochemistry staining from transplant tumor tissue (Fig.5C) selected for therapy groups VCR plus mAb, VCR plus siRNA, and VCR plus ASO showed a remarkable decreased expression of MGr1-Ag/37LRP compared to the respective control groups. The expression of MGr1-Ag/37LRP and pFAK, p-AKT, p-ERK, and Bcl-2 in vivo were also detected in therapy groups of VCR plus mAb, VCR plus siRNA, and VCR plus ASO. In Figure5(B), Western blot analysis showed a remarkable decreased expression of MGr1-Ag/37LRP and inhibited the phosphorylation of FAK, AKT, and ERK, as well as subsequently downregulating expression of the Bcl-2 protein compared to the respective control groups. These data suggested that mAb, siRNA, and ASO, all of which target MGr1-Ag/37LRP, can enhance the sensitivity to chemotherapeutic drugs significantly in xenograft and inhibition of FAK, PI3K, and ERK might be another strategy to overcome CAM-DR.


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 MGr1-Ag/37LRP mAb, siRNA, and antisense oligonucleotide (ASO) treatment on SGC7901/VCR tumor growth and chemosensitivity in vivo. (A) Mice bearing SGC7901/VCR tumors were randomly selected for treatment with vincristine (VCR) plus mAb (VAb), VCR plus siRNA (VSM), VCR plus ASO (VAS), VCR alone (VCR), VCR plus scrambled siRNA (VSP), VCR plus scrambled ASO (VNS), VCR plus control antibody (VIg), or the untreated group (TB). When SGC7901/VCR tumors reached 200 mm3, 0.2 mg/kg siRNA or scrambled siRNA, 100 mg/kg antibody MGr1 or control antibody, 10 mg/kg ASO or scrambled ASO were injected once every 3 days for 36 days. From days 7–14 and 21–28, 0.6 mg/kg VCR was given weekly by tail vein injection. Tumor volume was measured every 4 days and calculated by the formula: length × width × depth × 0.5236. Each point represents the mean tumor volume in each experimental group containing 10 mice. *P > 0.05 in each control group; #P < 0.05 versus respective controls, by least significant difference t-test. (B) Protein expression of MGr1-Ag/37LRP, phosphorylated focal adhesion kinase (pFAK), total FAK (tFAK), pAKT, tAKT, and Bcl-2 in vivo. Lysates were resolved by SDS-PAGE, and MGr1-Ag/37LRP, pFAK, tFAK, pAKT, tAKT, pERK, and tERK, Bcl-2 or β-actin (as indicated) was assessed by Western blot analysis. Representative experiments are shown from three for each cell type. (C) Immunohistochemical staining for MGr1-Ag/37LRP of paraffin-embedded sections from s.c. tumors: (a) negative control group; (b) TB group; (c) VCR group; (d) VAb group; (e) VSM group; (f) VAS group; (g) VIg group; (h) VSP group; (i) VNS group (original magnification, 200×). The results shown are representative of three independent experiments.
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fig05: Effect of MGr1-Ag/37LRP mAb, siRNA, and antisense oligonucleotide (ASO) treatment on SGC7901/VCR tumor growth and chemosensitivity in vivo. (A) Mice bearing SGC7901/VCR tumors were randomly selected for treatment with vincristine (VCR) plus mAb (VAb), VCR plus siRNA (VSM), VCR plus ASO (VAS), VCR alone (VCR), VCR plus scrambled siRNA (VSP), VCR plus scrambled ASO (VNS), VCR plus control antibody (VIg), or the untreated group (TB). When SGC7901/VCR tumors reached 200 mm3, 0.2 mg/kg siRNA or scrambled siRNA, 100 mg/kg antibody MGr1 or control antibody, 10 mg/kg ASO or scrambled ASO were injected once every 3 days for 36 days. From days 7–14 and 21–28, 0.6 mg/kg VCR was given weekly by tail vein injection. Tumor volume was measured every 4 days and calculated by the formula: length × width × depth × 0.5236. Each point represents the mean tumor volume in each experimental group containing 10 mice. *P > 0.05 in each control group; #P < 0.05 versus respective controls, by least significant difference t-test. (B) Protein expression of MGr1-Ag/37LRP, phosphorylated focal adhesion kinase (pFAK), total FAK (tFAK), pAKT, tAKT, and Bcl-2 in vivo. Lysates were resolved by SDS-PAGE, and MGr1-Ag/37LRP, pFAK, tFAK, pAKT, tAKT, pERK, and tERK, Bcl-2 or β-actin (as indicated) was assessed by Western blot analysis. Representative experiments are shown from three for each cell type. (C) Immunohistochemical staining for MGr1-Ag/37LRP of paraffin-embedded sections from s.c. tumors: (a) negative control group; (b) TB group; (c) VCR group; (d) VAb group; (e) VSM group; (f) VAS group; (g) VIg group; (h) VSP group; (i) VNS group (original magnification, 200×). The results shown are representative of three independent experiments.
Mentions: We then evaluated the effects of MGr1-Ag/37LRP mAb, siRNA, and ASO treatment on the chemotherapy of SGC7901/VCR tumors in vivo. Figure5(A) shows that therapy groups VCR plus mAb, VCR plus siRNA, and VCR plus ASO significantly reduced SGC7901/VCR tumor volume by 50% from days 16 to 40 compared to treatment with VCR alone, VCR plus control antibody, VCR plus scrambled siRNA, and VCR plus scrambled ASO, and the untreated group. In addition, after first treatment with VCR, from days 12 to 20, monotherapy of VCR significantly reduced SGC7901/VCR tumor volume compared to the untreated group. However, after first treatment with VCR, from days 24 to 40, there was no difference in SGC7901/VCR tumor volume between the VCR monotherapy group and the untreated group. Immunochemistry staining from transplant tumor tissue (Fig.5C) selected for therapy groups VCR plus mAb, VCR plus siRNA, and VCR plus ASO showed a remarkable decreased expression of MGr1-Ag/37LRP compared to the respective control groups. The expression of MGr1-Ag/37LRP and pFAK, p-AKT, p-ERK, and Bcl-2 in vivo were also detected in therapy groups of VCR plus mAb, VCR plus siRNA, and VCR plus ASO. In Figure5(B), Western blot analysis showed a remarkable decreased expression of MGr1-Ag/37LRP and inhibited the phosphorylation of FAK, AKT, and ERK, as well as subsequently downregulating expression of the Bcl-2 protein compared to the respective control groups. These data suggested that mAb, siRNA, and ASO, all of which target MGr1-Ag/37LRP, can enhance the sensitivity to chemotherapeutic drugs significantly in xenograft and inhibition of FAK, PI3K, and ERK might be another strategy to overcome CAM-DR.

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