title: Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells.
abstract: Kinase suppressor of Ras 1 (KSR1) is a scaffold protein that modulates the activation of the oncogenic mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. Ginkgo biloba extract (EGb) 761 has been demonstrated to possess antitumor activity that may be related to the KSR1-mediated ERK signaling pathway. However, the roles and its underlying mechanism in gastric cancer are unclear. In the present study, 62 gastric cancer and matched normal tissues were exploited for immunohistochemistry and real-time fluorescent quantitative PCR detection. Results of the immunohistochemistry showed that the expression of ERK1/2 and p-ERK1/2 was correlated to the expression of KSR1 and p-KSR1 in the gastric cancer tissues, and the overexpression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 was significantly associated with histological grade, TNM stage, lymph node and distant metastasis. Compared with the normal tissues, the relative mRNA copy values of KSR1, ERK1 and ERK2 in the cancer tissues were 2.43 ± 0.49, 2.10 ± 0.44 and 3.65 ± 0.94. In addition, the expression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 in human gastric cancer multidrug resistant SGC-7901/CDDP cells was higher than that in the SGC-7901 cells as detected by the methods of immunocytochemistry and western blot analysis. EGb 761 not only suppressed expression of these proteins induced by cisplatin (CDDP) and etoposide in SGC-7901 cells, but also inhibited expression of these proteins in the SGC-7901/CDDP cells. Meanwhile, the proliferation-suppressing and apoptosis-inducing capacities of CDDP and etoposide were enhanced following combined treatment with EGb 761. Moreover, EGb 761 reduced the malondialdehyde (MDA) content and elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tumor cells. These results confirmed that activation of the KSR1-mediated ERK1/2 signaling pathway may contribute to tumorigenesis, metastasis and chemoresistance of human gastric cancer. EGb 761 enhanced the chemotherapy sensitivity and reversed the chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells, and the underlying mechanism may be related to its antioxidative activity.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Shi-Quan
authors.initials: SQ
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Meng-Bin
authors.initials: MB
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Zhuge
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Ye-Bo
authors.initials: YB
authors.lastname: Mao
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Lai
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.
authors.forename: Jie-An
authors.initials: JA
authors.lastname: Huang
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D056915:DNA Copy Number Variations / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005047:Etoposide; D015972:Gene Expression Regulation, Neoplastic; D020441:Ginkgo biloba / Q000737:chemistry; D006801:Humans; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage* / Q000737:chemistry; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D010936:Plant Extracts; D005047:Etoposide; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin