MGr1-Ag/37LRP induces cell adhesion-mediated drug resistance through FAK/PI3K and MAPK pathway in gastric cancer.
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.
Affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.Show MeSH
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Mentions: To study the functional role of MGr1-Ag/37LRP in CAM-DR in GC, mAb-, ASO-, or siRNA-induced inhibition of MGr1-Ag/37LRP was determined by Western blot analysis. As shown in Figure4(a), treatment of SGC7901/VCR cells with ASO significantly reduced MGr1-Ag/37LRP protein levels by up to 75% in a dose-dependent manner, whereas MGr1-Ag/37LRP protein expression was not significantly suppressed by scrambled oligonucleotide. Similiar, MGr1-Ag expression was also inhibited at a dose-dependent manner using 10−3–1 nmol/L siRNA and 0.5–10 mg/L mAb. The cell adhesion assay, in vitro drug sensitivity assay, and annexin V/propidium iodide staining were used to exploit the MDR phenotype by blocking MGr1-Ag/37LRP with mAb, siRNA, ASO after adhesion to LN and control component (BSA) (Fig.4b–d). SGC7901/VCR cells transfected with siRNA (1 nmol/L), mAb (10 mg/L), and ASO (40 nM) showed significantly decreased mean adhesion cell number than that of control cells after adhesion to LN. Similarly, SGC7901/VCR cells transfected with siRNA (1 nmol/L), mAb (10 mg/L), and ASO (40 nM) showed significant increased IC50 values of VCR and 5-fluorouracil (5-FU) (Fig.4c), and decreased apoptotic index values in the same conditions (Fig.4d). These results suggested that inhibition of MGr1-Ag expression could partly reverse the CAM-DR phenotype in vitro.
Affiliation: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.